Methylmalonyl-CoA mutase: Difference between revisions

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'''Methylmalonyl-CoA mutase (MCM), mitochondrial''', also known as '''methylmalonyl-CoA isomerase''', is a protein that in humans is encoded by the ''MUT'' gene. This [[vitamin B12]]-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in ''MUT'' gene may lead to various types of [[methylmalonic aciduria]].<ref name=":0">{{Cite journal|last=Keyfi|first=F.|last2=Sankian|first2=M.|last3=Moghaddassian|first3=M.|last4=Rolfs|first4=A.|last5=Varasteh|first5=A. R.|date=2016-01-15|title=Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency|journal=Gene|volume=576|issue=1 Pt 2|pages=208–213|doi=10.1016/j.gene.2015.10.002|issn=1879-0038|pmid=26449400}}</ref>
'''Methylmalonyl-CoA mutase (MCM), mitochondrial''', also known as '''methylmalonyl-CoA isomerase''', is a protein that in humans is encoded by the ''MUT'' gene. This [[vitamin B12]]-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in ''MUT'' gene may lead to various types of [[methylmalonic aciduria]].<ref name=":0">{{cite journal | vauthors = Keyfi F, Sankian M, Moghaddassian M, Rolfs A, Varasteh AR | title = Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency | journal = Gene | volume = 576 | issue = 1 Pt 2 | pages = 208–13 | date = January 2016 | pmid = 26449400 | doi = 10.1016/j.gene.2015.10.002 }}</ref>


MCM was first identified in [[rat]] [[liver]] and [[sheep]] [[kidney]] in 1955. In its latent form, it is 750 [[amino acids]] in length. Upon entry to the mitochondria, the 32 amino acid mitochondrial leader sequence at the N-terminus of the protein is cleaved, forming the fully processed monomer. The monomers then associate into homodimers, and bind AdoCbl (one for each monomer active site) to form the final, active [[holoenzyme]] form.<ref name="pmid19699272">{{cite journal |vauthors=Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O |title=Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain |journal=[[Neuroscience (journal)|Neuroscience]] |volume=164 |issue=2 |pages=578–87 |year=2009 |pmid=19699272 |doi=10.1016/j.neuroscience.2009.08.028 |url=http://linkinghub.elsevier.com/retrieve/pii/S0306-4522(09)01385-2}}</ref>
MCM was first identified in [[rat]] [[liver]] and [[sheep]] [[kidney]] in 1955. In its latent form, it is 750 [[amino acids]] in length. Upon entry to the mitochondria, the 32 amino acid mitochondrial leader sequence at the N-terminus of the protein is cleaved, forming the fully processed monomer. The monomers then associate into homodimers, and bind AdoCbl (one for each monomer active site) to form the final, active [[holoenzyme]] form.<ref name="pmid19699272">{{cite journal | vauthors = Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O | title = Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain | journal = Neuroscience | volume = 164 | issue = 2 | pages = 578–87 | date = December 2009 | pmid = 19699272 | doi = 10.1016/j.neuroscience.2009.08.028 | url = http://linkinghub.elsevier.com/retrieve/pii/S0306-4522(09)01385-2 }}</ref>


==Structure==
== Structure ==


===Gene===
===Gene===


The ''MUT'' gene lies on the [[chromosome]] location of 6p12.3 and consists of 13 [[exons]], spanning over 35kb.<ref>{{Cite journal|last=Chandler|first=R. J.|last2=Venditti|first2=C. P.|date=2016-10-01|title=Genetic and genomic systems to study methylmalonic acidemia|journal=Molecular Genetics and Metabolism|volume=86|issue=1–2|pages=34–43|doi=10.1016/j.ymgme.2005.07.020|issn=1096-7192|pmc=2657357|pmid=16182581}}</ref>
The ''MUT'' gene lies on the [[chromosome]] location of 6p12.3 and consists of 13 [[exons]], spanning over 35kb.<ref>{{cite journal | vauthors = Chandler RJ, Venditti CP | title = Genetic and genomic systems to study methylmalonic acidemia | journal = Molecular Genetics and Metabolism | volume = 86 | issue = 1-2 | pages = 34–43 | date = 2016-10-01 | pmid = 16182581 | pmc = 2657357 | doi = 10.1016/j.ymgme.2005.07.020 }}</ref>


===Protein===
===Protein===


The mature enzyme is a homodimer with the N-terminal CoA binding domain and the C- terminal cobalamin-binding domain.<ref>{{Cite journal|last=Drennan|first=C. L.|last2=Matthews|first2=R. G.|last3=Rosenblatt|first3=D. S.|last4=Ledley|first4=F. D.|last5=Fenton|first5=W. A.|last6=Ludwig|first6=M. L.|date=1996-05-28|title=Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=93|issue=11|pages=5550–5555|issn=0027-8424|pmc=39284|pmid=8643613|doi=10.1073/pnas.93.11.5550}}</ref>
The mature enzyme is a homodimer with the N-terminal CoA binding domain and the C- terminal cobalamin-binding domain.<ref>{{cite journal | vauthors = Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML | title = Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5550–5 | date = May 1996 | pmid = 8643613 | pmc = 39284 | doi = 10.1073/pnas.93.11.5550 }}</ref>


==Function==
== Function ==


Methylmalonyl-CoA mutase is expressed in high concentrations in the [[kidney]], in intermediate concentrations in the [[heart]], [[ovaries]], [[brain]], [[muscle]], and liver, and in low concentrations in the [[spleen]].<ref name="pmid19699272" /> The enzyme can be found all throughout the [[central nervous system]] (CNS).<ref name="pmid19699272" /> MCM resides in the mitochondria, where a number of substances, including the [[branched-chain amino acids]] [[isoleucine]] and [[valine]], as well as [[methionine]], [[threonine]], [[thymine]] and odd-chain [[fatty acids]], are metabolized via methylmalonate semialdehyde (MMlSA) or propionyl-CoA (Pr-CoA) to a common compound - methylmalonyl-CoA (MMl-CoA).
Methylmalonyl-CoA mutase is expressed in high concentrations in the [[kidney]], in intermediate concentrations in the [[heart]], [[ovaries]], [[brain]], [[muscle]], and liver, and in low concentrations in the [[spleen]].<ref name="pmid19699272" /> The enzyme can be found all throughout the [[central nervous system]] (CNS).<ref name="pmid19699272" /> MCM resides in the mitochondria, where a number of substances, including the [[branched-chain amino acids]] [[isoleucine]] and [[valine]], as well as [[methionine]], [[threonine]], [[thymine]] and odd-chain [[fatty acids]], are metabolized via methylmalonate semialdehyde (MMlSA) or propionyl-CoA (Pr-CoA) to a common compound - methylmalonyl-CoA (MMl-CoA).
MCM catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA, requiring cobalamin (vitamin B12) in the form of adenosylcobalamin (AdoCbl) as a cofactor. As an important step in propionate catabolism, this reaction is required for the degradation of odd-chain [[fatty acids]], the amino acids [[valine]], [[isoleucine]], [[methionine]], and [[threonine]], and [[cholesterol]],<ref>{{Cite journal|last=Martínez|first=Maria Angeles|last2=Rincón|first2=Ana|last3=Desviat|first3=Lourdes R.|last4=Merinero|first4=Begoña|last5=Ugarte|first5=Magdalena|last6=Pérez|first6=Belén|date=2005-04-01|title=Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants|journal=Molecular Genetics and Metabolism|volume=84|issue=4|pages=317–325|doi=10.1016/j.ymgme.2004.11.011|issn=1096-7192|pmid=15781192}}</ref> funneling metabolites from the breakdown of these amino acids into the [[tricarboxylic acid cycle]].<ref>{{Cite journal|last=Forny|first=Patrick|last2=Froese|first2=D. Sean|last3=Suormala|first3=Terttu|last4=Yue|first4=Wyatt W.|last5=Baumgartner|first5=Matthias R.|date=2014-12-01|title=Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency|journal=Human Mutation|volume=35|issue=12|pages=1449–1458|doi=10.1002/humu.22633|issn=1098-1004|pmc=4441004|pmid=25125334}}</ref>
MCM catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA, requiring cobalamin (vitamin B12) in the form of adenosylcobalamin (AdoCbl) as a cofactor. As an important step in propionate catabolism, this reaction is required for the degradation of odd-chain [[fatty acids]], the amino acids [[valine]], [[isoleucine]], [[methionine]], and [[threonine]], and [[cholesterol]],<ref>{{cite journal | vauthors = Martínez MA, Rincón A, Desviat LR, Merinero B, Ugarte M, Pérez B | title = Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants | journal = Molecular Genetics and Metabolism | volume = 84 | issue = 4 | pages = 317–25 | date = April 2005 | pmid = 15781192 | doi = 10.1016/j.ymgme.2004.11.011 }}</ref> funneling metabolites from the breakdown of these amino acids into the [[tricarboxylic acid cycle]].<ref>{{cite journal | vauthors = Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR | title = Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency | journal = Human Mutation | volume = 35 | issue = 12 | pages = 1449–58 | date = December 2014 | pmid = 25125334 | pmc = 4441004 | doi = 10.1002/humu.22633 }}</ref>


Methylmalonyl-CoA mutase catalyzes the following reaction:
Methylmalonyl-CoA mutase catalyzes the following reaction:
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==Clinical significance==
==Clinical significance==


A deficiency of this enzyme is responsible for an inherited disorder of metabolism, [[Methylmalonyl-CoA mutase deficiency]], which is one of the causes of [[methylmalonic acidemia]] (also referred to as methylmalonic aciduria or MMA). MMA is an [[autosomal recessive]] inherited inborn error of metabolism, characterized by recurrent episodes of vomiting, lethargy, profound [[ketoacidosis]], [[hyperammonemia]], and [[pancytopenia]] in infancy, and may cause early death. Complications include [[cardiomyopathy]], [[metabolic stroke]], [[pancreatitis]], and [[progressive renal failure]].<ref name=":0" /><ref>{{Cite journal|last=Dündar|first=Halil|last2=Özgül|first2=Riza Köksal|last3=Güzel-Ozantürk|first3=Ayşegül|last4=Dursun|first4=Ali|last5=Sivri|first5=Serap|last6=Aliefendioğlu|first6=Didem|last7=Coşkun|first7=Turgay|last8=Tokatli|first8=Ayşegül|date=2012-08-01|title=Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations|journal=Molecular Genetics and Metabolism|volume=106|issue=4|pages=419–423|doi=10.1016/j.ymgme.2012.05.014|issn=1096-7206|pmid=22727635}}</ref>
A deficiency of this enzyme is responsible for an inherited disorder of metabolism, [[Methylmalonyl-CoA mutase deficiency]], which is one of the causes of [[methylmalonic acidemia]] (also referred to as methylmalonic aciduria or MMA). MMA is an [[autosomal recessive]] inherited inborn error of metabolism, characterized by recurrent episodes of vomiting, lethargy, profound [[ketoacidosis]], [[hyperammonemia]], and [[pancytopenia]] in infancy, and may cause early death. Complications include [[cardiomyopathy]], [[metabolic stroke]], [[pancreatitis]], and [[progressive renal failure]].<ref name=":0" /><ref>{{cite journal | vauthors = Dündar H, Özgül RK, Güzel-Ozantürk A, Dursun A, Sivri S, Aliefendioğlu D, Coşkun T, Tokatli A | title = Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations | journal = Molecular Genetics and Metabolism | volume = 106 | issue = 4 | pages = 419–23 | date = August 2012 | pmid = 22727635 | doi = 10.1016/j.ymgme.2012.05.014 }}</ref>


Either mutations to the gene ''MUT'' (encodes methylmalonyl-CoA mutase), or ''MMAA'' (encodes a chaperone protein of methylmalonyl-CoA mutase, ''MMAA'' protein) can lead to methylmalonyl acidemia.<ref name="pmid21138732">{{cite journal|year=2011|title=Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein|url=http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(10)02216-3|journal=[[Biochem. Biophys. Res. Commun.]]|volume=404|issue=1|pages=443–7|doi=10.1016/j.bbrc.2010.11.141|pmid=21138732|vauthors=Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME}}</ref> Mutations to ''MUT'' can be categorized as either ''MUT<sup>0</sup>'' (demonstrates no activity even in presence of excess AdoCbl), or ''MUT<sup>1</sup>'' (demonstrates very low activity in presence of excess AdoCbl).<ref name="pmid8643613">{{cite journal |vauthors=Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML |title=Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase |journal=[[Proc. Natl. Acad. Sci. U.S.A.]] |volume=93 |issue=11 |pages=5550–5 |year=1996 |pmid=8643613 |pmc=39284 |doi= 10.1073/pnas.93.11.5550|url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8643613}}</ref> Over half of the mutations of ''MUT'' are [[missense mutations]]<ref name="pmid25125334">{{cite journal |vauthors=Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR |title=Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency |journal=[[Hum. Mutat.]] |volume=35 |issue=12 |pages=1449–58 |year=2014 |pmid=25125334 |doi=10.1002/humu.22633 |url=https://dx.doi.org/10.1002/humu.22633 |pmc=4441004}}</ref> while [[nonsense mutations]] comprise a significant remaining fraction (approximately 14%)<ref name="pmid23041189">{{cite journal |vauthors=Buck NE, Wood LR, Hamilton NJ, Bennett MJ, Peters HL |title=Treatment of a methylmalonyl-CoA mutase stopcodon mutation |journal=[[Biochem. Biophys. Res. Commun.]] |volume=427 |issue=4 |pages=753–7 |year=2012 |pmid=23041189 |doi=10.1016/j.bbrc.2012.09.133 |url=http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(12)01911-0}}</ref>
Either mutations to the gene ''MUT'' (encodes methylmalonyl-CoA mutase), or ''MMAA'' (encodes a chaperone protein of methylmalonyl-CoA mutase, ''MMAA'' protein) can lead to methylmalonyl acidemia.<ref name="pmid21138732">{{cite journal | vauthors = Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME | title = Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein | journal = Biochemical and Biophysical Research Communications | volume = 404 | issue = 1 | pages = 443–7 | date = January 2011 | pmid = 21138732 | doi = 10.1016/j.bbrc.2010.11.141 | url = http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(10)02216-3 }}</ref> Mutations to ''MUT'' can be categorized as either ''MUT<sup>0</sup>'' (demonstrates no activity even in presence of excess AdoCbl), or ''MUT<sup>1</sup>'' (demonstrates very low activity in presence of excess AdoCbl).<ref name="pmid8643613">{{cite journal | vauthors = Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML | title = Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5550–5 | date = May 1996 | pmid = 8643613 | pmc = 39284 | doi = 10.1073/pnas.93.11.5550 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8643613 }}</ref> Over half of the mutations of ''MUT'' are [[missense mutations]]<ref name="pmid25125334">{{cite journal | vauthors = Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR | title = Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency | journal = Human Mutation | volume = 35 | issue = 12 | pages = 1449–58 | date = December 2014 | pmid = 25125334 | pmc = 4441004 | doi = 10.1002/humu.22633 }}</ref> while [[nonsense mutations]] comprise a significant remaining fraction (approximately 14%)<ref name="pmid23041189">{{cite journal | vauthors = Buck NE, Wood LR, Hamilton NJ, Bennett MJ, Peters HL | title = Treatment of a methylmalonyl-CoA mutase stopcodon mutation | journal = Biochemical and Biophysical Research Communications | volume = 427 | issue = 4 | pages = 753–7 | date = November 2012 | pmid = 23041189 | doi = 10.1016/j.bbrc.2012.09.133 | url = http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(12)01911-0 }}</ref>


Common treatment methods for MMA include a [[liver transplant]] or a liver and [[kidney transplant]] to combat the [[renal disease]] of methylmalonic acidemia. However, detrimental neurological effects can continue to plague patients even after a successful operation. It is thought that this is due to the widespread presence of methylmalonyl-CoA mutase throughout the central nervous system. Due to the loss of functionality of the enzyme, substrate levels build up in the CNS. The substrate, L-methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid that, due to the poor dicarboxylic acid transport capacities of the blood-brain barrier, is effectively trapped within the CNS, leading to neurological debilitation. To combat these effects perioperative anti-catabolic regimes and no diet discontinuation are recommended.<ref name="pmid19699272"/>
Common treatment methods for MMA include a [[liver transplant]] or a liver and [[kidney transplant]] to combat the [[renal disease]] of methylmalonic acidemia. However, detrimental neurological effects can continue to plague patients even after a successful operation. It is thought that this is due to the widespread presence of methylmalonyl-CoA mutase throughout the central nervous system. Due to the loss of functionality of the enzyme, substrate levels build up in the CNS. The substrate, L-methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid that, due to the poor dicarboxylic acid transport capacities of the blood-brain barrier, is effectively trapped within the CNS, leading to neurological debilitation. To combat these effects perioperative anti-catabolic regimes and no diet discontinuation are recommended.<ref name="pmid19699272"/>


''MUT'' has also been linked to [[bovine tuberculosis]] (bTB), a form of [[tuberculosis]] that affects mostly [[livestock]] and accounts for 10% of human cases.<ref name="pmid21084167">{{cite journal |vauthors=de la Fuente J, Gortazar C, Vicente J, Villar M |title=Host expression of methylmalonyl-CoA mutase and tuberculosis: a missing link? |journal=[[Med. Hypotheses]] |volume=76 |issue=3 |pages=361–4 |year=2011 |pmid=21084167 |doi=10.1016/j.mehy.2010.10.040 |url=http://linkinghub.elsevier.com/retrieve/pii/S0306-9877(10)00453-6}}</ref>{{ums|date=November 2017}} It has been proposed that high ''MUT'' expression (thus high methylmalonyl-CoA mutase levels) leads to lower cholesterol levels which increases resistance to bTB and affords an improved response to the [[BCG vaccine]].<ref name="pmid21084167"/>{{ums|date=November 2017}}
''MUT'' has also been linked to [[bovine tuberculosis]] (bTB), a form of [[tuberculosis]] that affects mostly [[livestock]] and accounts for 10% of human cases.<ref name="pmid21084167">{{cite journal | vauthors = de la Fuente J, Gortazar C, Vicente J, Villar M | title = Host expression of methylmalonyl-CoA mutase and tuberculosis: a missing link? | journal = Medical Hypotheses | volume = 76 | issue = 3 | pages = 361–4 | date = March 2011 | pmid = 21084167 | doi = 10.1016/j.mehy.2010.10.040 | url = http://linkinghub.elsevier.com/retrieve/pii/S0306-9877(10)00453-6 }}</ref>{{ums|date=November 2017}} It has been proposed that high ''MUT'' expression (thus high methylmalonyl-CoA mutase levels) leads to lower cholesterol levels which increases resistance to bTB and affords an improved response to the [[BCG vaccine]].<ref name="pmid21084167"/>{{ums|date=November 2017}}


The [[murine]] model has proven an adequate and accurate way of studying the effects of MMA, and potential treatment methods.<ref name="pmid23046887">{{cite journal |vauthors=Chandler RJ, Venditti CP |title=Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA) |journal=[[Mol. Genet. Metab.]] |volume=107 |issue=3 |pages=617–9 |year=2012 |pmid=23046887 |pmc=3522145 |doi=10.1016/j.ymgme.2012.09.019 |url=http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(12)00360-5}}</ref><ref name="pmid23898205">{{cite journal |vauthors=Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP |title=Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia |journal=[[Proc. Natl. Acad. Sci. U.S.A.]] |volume=110 |issue=33 |pages=13552–7 |year=2013 |pmid=23898205 |pmc=3746875 |doi=10.1073/pnas.1302764110 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=23898205}}</ref>
The [[murine]] model has proven an adequate and accurate way of studying the effects of MMA, and potential treatment methods.<ref name="pmid23046887">{{cite journal | vauthors = Chandler RJ, Venditti CP | title = Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA) | journal = Molecular Genetics and Metabolism | volume = 107 | issue = 3 | pages = 617–9 | date = November 2012 | pmid = 23046887 | pmc = 3522145 | doi = 10.1016/j.ymgme.2012.09.019 | url = http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(12)00360-5 }}</ref><ref name="pmid23898205">{{cite journal | vauthors = Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP | title = Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 33 | pages = 13552–7 | date = August 2013 | pmid = 23898205 | pmc = 3746875 | doi = 10.1073/pnas.1302764110 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=23898205 }}</ref>


==Mechanism==
==Mechanism==
[[Image:MUT.png|490px|MCM's reaction mechanism|thumb|left]]  
[[Image:MUT.png|490px|MCM's reaction mechanism|thumb|left]]  
The MCM reaction mechanism begins with homolytic cleavage of AdoB12's C-[[cobalt|Co]](III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. The Co ion, therefore, fluctuates between its Co(III) and Co(II) oxidation states [the two states are spectroscopically distinguishable: Co(III) is red and diamagnetic (no unpaired electrons), whereas Co(II) is yellow and paramagnetic (unpaired electrons)]. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible free radical generator. The C-Co(III) bond is well suited to this function because it is inherently weak (dissociation energy = 109 kJ/mol) and appears to be further weakened through steric interactions with the enzyme. A [[homolysis (chemistry)|homolytic cleavage]] reaction is unusual in biology; most other biological bond cleavage reactions occur via [[heterolysis (chemistry)|heterolytic cleavage]] (in which the electron pair forming the cleaved bond is fully acquired by one of the separating atoms).
The MCM reaction mechanism begins with homolytic cleavage of AdoB12's C-[[cobalt|Co]](III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. The Co ion, therefore, fluctuates between its Co(III) and Co(II) oxidation states [the two states are spectroscopically distinguishable: Co(III) is red and diamagnetic (no unpaired electrons), whereas Co(II) is yellow and paramagnetic (unpaired electrons)]. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible generator of a [[free radical]]. The C-Co(III) bond is weak, with a dissociation energy = 109 kJ/mol, and appears to be further weakened through steric interactions with the enzyme. The [[homolysis (chemistry)|homolytic]] reaction is unusual in biology, as is the presence of a metal-carbon bond.


Methylmalonyl-CoA mutase is a member of the [[isomerase]] subfamily of adenosylcobalamin-dependent enzymes. Furthermore, it is classified as class I, as it is a ‘DMB-off’/’His-on’ enzyme. This refers to the nature of the AdoCbl cofactor in the active site of methylmalonyl CoA.<ref name="pmid22661206">{{cite journal |vauthors=Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME |title=Role of vitamin B12 on methylmalonyl-CoA mutase activity |journal=[[J Zhejiang Univ Sci B]] |volume=13 |issue=6 |pages=423–37 |year=2012 |pmid=22661206 |pmc=3370288 |doi=10.1631/jzus.B1100329 |url=http://www.zju.edu.cn/jzus/article.php?doi=10.1631/jzus.B1100329}}</ref> AdoCbl is composed of a central [[cobalt]]-containing [[Corrin ring]], an upper axial ligand (β-axial ligand), and a lower axial ligand (α-axial ligand). Both axial ligands are initially bonded to the central cobalt atom. In methylmalonyl-CoA mutase the β-axial ligand is 5’-deoxy-5’-adenosine and is involved in the [[free radical]] chemistry of the reaction. The α-axial ligand is 5,6-dimethylbenzimidazole (DMB) and is involved in organizing the active site to enable [[Histidine]]-610 to bond with Co, instead of DMB (the reason for the ‘DMB-off’/’His-on’ notation).<ref name="pmid22661206"/> The Histidine-610 residue is critical to enzyme functionality. Its binding increases the rate of homolytic β-axial ligand – Co bond breakage by a factor of 10<sup>12</sup>.<ref name="pmid11893736">{{cite journal |vauthors=Vlasie M, Chowdhury S, Banerjee R |title=Importance of the histidine ligand to coenzyme B12 in the reaction catalyzed by methylmalonyl-CoA mutase |journal=[[J. Biol. Chem.]] |volume=277 |issue=21 |pages=18523–7 |year=2002 |pmid=11893736 |doi=10.1074/jbc.M111809200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11893736}}</ref>
Methylmalonyl-CoA mutase is a member of the [[isomerase]] subfamily of adenosylcobalamin-dependent enzymes. Furthermore, it is classified as class I, as it is a ‘DMB-off’/’His-on’ enzyme. This refers to the nature of the AdoCbl cofactor in the active site of methylmalonyl CoA.<ref name="pmid22661206">{{cite journal | vauthors = Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME | title = Role of vitamin B12 on methylmalonyl-CoA mutase activity | journal = Journal of Zhejiang University. Science. B | volume = 13 | issue = 6 | pages = 423–37 | date = June 2012 | pmid = 22661206 | pmc = 3370288 | doi = 10.1631/jzus.B1100329 | url = http://www.zju.edu.cn/jzus/article.php?doi=10.1631/jzus.B1100329 }}</ref> AdoCbl is composed of a central [[cobalt]]-containing [[corrin ring]], an upper axial ligand (β-axial ligand), and a lower axial ligand (α-axial ligand). In methylmalonyl-CoA mutase, the β-axial ligand 5’-deoxy-5’-adenosine reversibly dissociated to give the [[deoxyadenosyl radical]]. The α-axial ligand 5,6-dimethylbenzimidazole (DMB) is involved in organizing the active site to enable [[histidine]]-610 to bond with Co, instead of DMB (the reason for the ‘DMB-off’/’His-on’ notation).<ref name="pmid22661206"/> Binding of histidine-610 residue increases the rate of homolytic β-axial ligand – Co bond breakage by a factor of 10<sup>12</sup>.<ref name="pmid11893736">{{cite journal | vauthors = Vlasie M, Chowdhury S, Banerjee R | title = Importance of the histidine ligand to coenzyme B12 in the reaction catalyzed by methylmalonyl-CoA mutase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 21 | pages = 18523–7 | date = May 2002 | pmid = 11893736 | doi = 10.1074/jbc.M111809200 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11893736 }}</ref>


[[File:Active site MCM colors.png|400px|thumb|right|MCM active site. Corrin ring and α-axial ligand (DMB): (yellow), β-axial ligand: (green), substrate/product: (cyan), residues interacting with β-axial ligand: glu370, asn366, gly91, ala139 (blue), residues interacting with substrate: gln197, his244, arg207, tyr89 (red), and his610: (orange).<ref name="pmid10387043">{{cite journal |vauthors=Mancia F, Smith GA, Evans PR |title=Crystal structure of substrate complexes of methylmalonyl-CoA mutase |journal=[[Biochemistry (journal)|Biochemistry]] |volume=38 |issue=25 |pages=7999–8005 |year=1999 |pmid=10387043 |doi=10.1021/bi9903852 |url=https://dx.doi.org/10.1021/bi9903852}}</ref> Rendered from PDB 4REQ.<ref name="pmid9655823">{{cite journal |vauthors=Mancia F, Evans PR |title=Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism |journal=[[Structure (journal)|Structure]] |volume=6 |issue=6 |pages=711–20 |year=1998 |pmid=9655823 |doi= 10.1016/s0969-2126(98)00073-2|url=}}</ref>]]
[[File:Active site MCM colors.png|400px|thumb|right|MCM active site. Corrin ring and α-axial ligand (DMB): (yellow), β-axial ligand: (green), substrate/product: (cyan), residues interacting with β-axial ligand: glu370, asn366, gly91, ala139 (blue), residues interacting with substrate: gln197, his244, arg207, tyr89 (red), and his610: (orange).<ref name="pmid10387043">{{cite journal | vauthors = Mancia F, Smith GA, Evans PR | title = Crystal structure of substrate complexes of methylmalonyl-CoA mutase | journal = Biochemistry | volume = 38 | issue = 25 | pages = 7999–8005 | date = June 1999 | pmid = 10387043 | doi = 10.1021/bi9903852 }}</ref> Rendered from PDB 4REQ.<ref name="pmid9655823">{{cite journal | vauthors = Mancia F, Evans PR | title = Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism | journal = Structure | volume = 6 | issue = 6 | pages = 711–20 | date = June 1998 | pmid = 9655823 | doi = 10.1016/s0969-2126(98)00073-2 }}</ref>]]
Other important residues of methylmalonyl-CoA mutase include Histidine-244, which acts as a general acid near the substrate and shields the radical species from side reactions involving oxygen,<ref name="pmid10551831">{{cite journal |vauthors=Maiti N, Widjaja L, Banerjee R |title=Proton transfer from histidine 244 may facilitate the 1,2 rearrangement reaction in coenzyme B(12)-dependent methylmalonyl-CoA mutase |journal=[[J. Biol. Chem.]] |volume=274 |issue=46 |pages=32733–7 |year=1999 |pmid=10551831 |doi= 10.1074/jbc.274.46.32733|url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10551831}}</ref> [[Glutamate]]-370, whose hydrogen bond with the 2’-OH group of the [[ribose]] of the β-axial ligand forces interaction between the β-axial ligand radical species and the substrate,<ref name="pmid22945861">{{cite journal |vauthors=Buckel W, Friedrich P, Golding BT |title=Hydrogen bonds guide the short-lived 5'-deoxyadenosyl radical to the place of action |journal=[[Angew. Chem. Int. Ed. Engl.]] |volume=51 |issue=40 |pages=9974–6 |year=2012 |pmid=22945861 |doi=10.1002/anie.201205299 |url=https://dx.doi.org/10.1002/anie.201205299}}</ref> and [[tyrosine]]-89 which stabilizes reactive radical intermediates and accounts for the stereo-selectivity of the enzyme.<ref name="pmid10387043"/><ref name="pmid9772164">{{cite journal |vauthors=Thomä NH, Meier TW, Evans PR, Leadlay PF |title=Stabilization of radical intermediates by an active-site tyrosine residue in methylmalonyl-CoA mutase |journal=[[Biochemistry (journal)|Biochemistry]] |volume=37 |issue=41 |pages=14386–93 |year=1998 |pmid=9772164 |doi=10.1021/bi981375o |url=https://dx.doi.org/10.1021/bi981375o}}</ref>
Other important residues of methylmalonyl-CoA mutase include Histidine-244, which acts as a general acid near the substrate and shields the radical species from side reactions involving oxygen,<ref name="pmid10551831">{{cite journal | vauthors = Maiti N, Widjaja L, Banerjee R | title = Proton transfer from histidine 244 may facilitate the 1,2 rearrangement reaction in coenzyme B(12)-dependent methylmalonyl-CoA mutase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 46 | pages = 32733–7 | date = November 1999 | pmid = 10551831 | doi = 10.1074/jbc.274.46.32733 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10551831 }}</ref> [[Glutamate]]-370, whose hydrogen bond with the 2’-OH group of the [[ribose]] of the β-axial ligand forces interaction between the β-axial ligand radical species and the substrate,<ref name="pmid22945861">{{cite journal | vauthors = Buckel W, Friedrich P, Golding BT | title = Hydrogen bonds guide the short-lived 5'-deoxyadenosyl radical to the place of action | journal = Angewandte Chemie | volume = 51 | issue = 40 | pages = 9974–6 | date = October 2012 | pmid = 22945861 | doi = 10.1002/anie.201205299 }}</ref> and [[tyrosine]]-89 which stabilizes reactive radical intermediates and accounts for the stereo-selectivity of the enzyme.<ref name="pmid10387043"/><ref name="pmid9772164">{{cite journal | vauthors = Thomä NH, Meier TW, Evans PR, Leadlay PF | title = Stabilization of radical intermediates by an active-site tyrosine residue in methylmalonyl-CoA mutase | journal = Biochemistry | volume = 37 | issue = 41 | pages = 14386–93 | date = October 1998 | pmid = 9772164 | doi = 10.1021/bi981375o }}</ref>


The processing protein, ''[[MMAA]]'' protein, fills the important role of aiding cofactor loading and exchange.<ref name="pmid21138732" /><ref name="pmid20876572">{{cite journal|year=2010|title=Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation|url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=20876572|journal=[[J. Biol. Chem.]]|volume=285|issue=49|pages=38204–13|doi=10.1074/jbc.M110.177717|pmc=2992254|pmid=20876572|vauthors=Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW}}</ref>  ''MMAA'' protein favors association with the MCM [[apoenzyme]], and allows for the transfer of the AdoCbl cofactor to the enzyme active site.<ref name="pmid20876572" /> Furthermore, if the bound AdoCbl accrues oxidative damage during normal functioning, ''MMAA'' protein fosters exchange of the damaged cofactor for a new AdoCbl via a [[Guanosine triphosphate|GTP]]-reliant pathway.<ref name="pmid21138732" /><ref name="pmid20876572" />
The processing protein, ''[[MMAA]]'' protein, fills the important role of aiding cofactor loading and exchange.<ref name="pmid21138732" /><ref name="pmid20876572">{{cite journal | vauthors = Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW | title = Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation | journal = The Journal of Biological Chemistry | volume = 285 | issue = 49 | pages = 38204–13 | date = December 2010 | pmid = 20876572 | pmc = 2992254 | doi = 10.1074/jbc.M110.177717 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=20876572 }}</ref>  ''MMAA'' protein favors association with the MCM [[apoenzyme]], and allows for the transfer of the AdoCbl cofactor to the enzyme active site.<ref name="pmid20876572" /> Furthermore, if the bound AdoCbl accrues oxidative damage during normal functioning, ''MMAA'' protein fosters exchange of the damaged cofactor for a new AdoCbl via a [[Guanosine triphosphate|GTP]]-reliant pathway.<ref name="pmid21138732" /><ref name="pmid20876572" />


==Interactions==
== Interactions ==


* [[MMAA]]<ref name=":1">{{Cite journal|last=Froese|first=D. Sean|last2=Kochan|first2=Grazyna|last3=Muniz|first3=João R. C.|last4=Wu|first4=Xuchu|last5=Gileadi|first5=Carina|last6=Ugochukwu|first6=Emelie|last7=Krysztofinska|first7=Ewelina|last8=Gravel|first8=Roy A.|last9=Oppermann|first9=Udo|date=2010-12-03|title=Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation|journal=The Journal of Biological Chemistry|volume=285|issue=49|pages=38204–38213|doi=10.1074/jbc.M110.177717|issn=1083-351X|pmc=2992254|pmid=20876572}}</ref>
* [[MMAA]]<ref name=":1">{{cite journal | vauthors = Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW | title = Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation | journal = The Journal of Biological Chemistry | volume = 285 | issue = 49 | pages = 38204–13 | date = December 2010 | pmid = 20876572 | pmc = 2992254 | doi = 10.1074/jbc.M110.177717 }}</ref>
* Vitamin B12<ref name=":1" />
* Vitamin B12<ref name=":1" />
* [[MeaB]] <ref>{{Cite journal|last=Padovani|first=Dominique|last2=Labunska|first2=Tetyana|last3=Banerjee|first3=Ruma|date=2006-06-30|title=Energetics of interaction between the G-protein chaperone, MeaB, and B12-dependent methylmalonyl-CoA mutase|journal=The Journal of Biological Chemistry|volume=281|issue=26|pages=17838–17844|doi=10.1074/jbc.M600047200|issn=0021-9258|pmid=16641088}}</ref>
* [[MeaB]] <ref>{{cite journal | vauthors = Padovani D, Labunska T, Banerjee R | title = Energetics of interaction between the G-protein chaperone, MeaB, and B12-dependent methylmalonyl-CoA mutase | journal = The Journal of Biological Chemistry | volume = 281 | issue = 26 | pages = 17838–44 | date = June 2006 | pmid = 16641088 | doi = 10.1074/jbc.M600047200 }}</ref>
* CoA-esters<ref>{{Cite journal|last=Taoka|first=S.|last2=Padmakumar|first2=R.|last3=Lai|first3=M. T.|last4=Liu|first4=H. W.|last5=Banerjee|first5=R.|date=1994-12-16|title=Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters|url=https://www.ncbi.nlm.nih.gov/pubmed/?term=7989334|journal=The Journal of Biological Chemistry|volume=269|issue=50|pages=31630–31634|issn=0021-9258|pmid=7989334}}</ref>
* CoA-esters<ref>{{cite journal | vauthors = Taoka S, Padmakumar R, Lai MT, Liu HW, Banerjee R | title = Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters | journal = The Journal of Biological Chemistry | volume = 269 | issue = 50 | pages = 31630–4 | date = December 1994 | pmid = 7989334 | url = https://www.ncbi.nlm.nih.gov/pubmed/?term=7989334 }}</ref>
* [[MMAB]]
* [[MMAB]]
* [[MMACHC]]
* [[MMACHC]]
* [[MMADHC]]
* [[MMADHC]]
{{clear}}
== References ==
{{reflist|32em}}


==References==
== Further reading ==
{{reflist}}
{{refbegin|32em}}
 
* {{cite journal | vauthors = Ledley FD, Rosenblatt DS | title = Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations | journal = Human Mutation | volume = 9 | issue = 1 | pages = 1–6 | year = 1997 | pmid = 8990001 | doi = 10.1002/(SICI)1098-1004(1997)9:1<1::AID-HUMU1>3.0.CO;2-E }}
==Further reading==
* {{cite journal | vauthors = Ludwig ML, Matthews RG | title = Structure-based perspectives on B12-dependent enzymes | journal = Annual Review of Biochemistry | volume = 66 | issue =  | pages = 269–313 | year = 1997 | pmid = 9242908 | doi = 10.1146/annurev.biochem.66.1.269 }}
{{refbegin | 2}}
* {{cite journal | vauthors = Lubrano R, Elli M, Rossi M, Travasso E, Raggi C, Barsotti P, Carducci C, Berloco P | title = Renal transplant in methylmalonic acidemia: could it be the best option? Report on a case at 10 years and review of the literature | journal = Pediatric Nephrology | volume = 22 | issue = 8 | pages = 1209–14 | date = August 2007 | pmid = 17401587 | doi = 10.1007/s00467-007-0460-z }}
{{PBB_Further_reading
* {{cite journal | vauthors = Frenkel EP, Kitchens RL | title = Intracellular localization of hepatic propionyl-CoA carboxylase and methylmalonyl-CoA mutase in humans and normal and vitamin B12 deficient rats | journal = British Journal of Haematology | volume = 31 | issue = 4 | pages = 501–13 | date = December 1975 | pmid = 24458 | doi = 10.1111/j.1365-2141.1975.tb00885.x }}
| citations =
* {{cite journal | vauthors = Crane AM, Jansen R, Andrews ER, Ledley FD | title = Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria | journal = The Journal of Clinical Investigation | volume = 89 | issue = 2 | pages = 385–91 | date = February 1992 | pmid = 1346616 | pmc = 442864 | doi = 10.1172/JCI115597 }}
*{{cite journal |vauthors=Ledley FD, Rosenblatt DS |title=Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations. |journal=Hum. Mutat. |volume=9 |issue= 1 |pages= 1–6 |year= 1997 |pmid= 8990001 |doi= 10.1002/(SICI)1098-1004(1997)9:1<1::AID-HUMU1>3.0.CO;2-E }}
* {{cite journal | vauthors = Crane AM, Martin LS, Valle D, Ledley FD | title = Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase | journal = Human Genetics | volume = 89 | issue = 3 | pages = 259–64 | date = May 1992 | pmid = 1351030 | doi = 10.1007/BF00220536 }}
*{{cite journal |vauthors=Ludwig ML, Matthews RG |title=Structure-based perspectives on B12-dependent enzymes. |journal=Annu. Rev. Biochem. |volume=66 |issue=  |pages= 269–313 |year= 1997 |pmid= 9242908 |doi= 10.1146/annurev.biochem.66.1.269 }}
* {{cite journal | vauthors = Raff ML, Crane AM, Jansen R, Ledley FD, Rosenblatt DS | title = Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation | journal = The Journal of Clinical Investigation | volume = 87 | issue = 1 | pages = 203–7 | date = January 1991 | pmid = 1670635 | pmc = 295026 | doi = 10.1172/JCI114972 }}
*{{cite journal   |vauthors=Lubrano R, Elli M, Rossi M, etal |title=Renal transplant in methylmalonic acidemia: could it be the best option? Report on a case at 10 years and review of the literature. |journal=Pediatr. Nephrol. |volume=22 |issue= 8 |pages= 1209–14 |year= 2007 |pmid= 17401587 |doi= 10.1007/s00467-007-0460-z }}
* {{cite journal | vauthors = Jansen R, Ledley FD | title = Heterozygous mutations at the mut locus in fibroblasts with mut0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning | journal = American Journal of Human Genetics | volume = 47 | issue = 5 | pages = 808–14 | date = November 1990 | pmid = 1977311 | pmc = 1683687 | doi =  }}
*{{cite journal |vauthors=Frenkel EP, Kitchens RL |title=Intracellular localization of hepatic propionyl-CoA carboxylase and methylmalonyl-CoA mutase in humans and normal and vitamin B12 deficient rats. |journal=Br. J. Haematol. |volume=31 |issue= 4 |pages= 501–13 |year= 1978 |pmid= 24458 |doi=10.1111/j.1365-2141.1975.tb00885.x }}
* {{cite journal | vauthors = Nham SU, Wilkemeyer MF, Ledley FD | title = Structure of the human methylmalonyl-CoA mutase (MUT) locus | journal = Genomics | volume = 8 | issue = 4 | pages = 710–6 | date = December 1990 | pmid = 1980486 | doi = 10.1016/0888-7543(90)90259-W }}
*{{cite journal |vauthors=Crane AM, Jansen R, Andrews ER, Ledley FD |title=Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria. |journal=J. Clin. Invest. |volume=89 |issue= 2 |pages= 385–91 |year= 1992 |pmid= 1346616 |doi=10.1172/JCI115597 | pmc=442864  }}
* {{cite journal | vauthors = Ledley FD, Lumetta M, Nguyen PN, Kolhouse JF, Allen RH | title = Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 10 | pages = 3518–21 | date = May 1988 | pmid = 2453061 | pmc = 280243 | doi = 10.1073/pnas.85.10.3518 }}
*{{cite journal |vauthors=Crane AM, Martin LS, Valle D, Ledley FD |title=Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase. |journal=Hum. Genet. |volume=89 |issue= 3 |pages= 259–64 |year= 1992 |pmid= 1351030 |doi=10.1007/BF00220536 }}
* {{cite journal | vauthors = Jansen R, Kalousek F, Fenton WA, Rosenberg LE, Ledley FD | title = Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction | journal = Genomics | volume = 4 | issue = 2 | pages = 198–205 | date = February 1989 | pmid = 2567699 | doi = 10.1016/0888-7543(89)90300-5 }}
*{{cite journal   |vauthors=Raff ML, Crane AM, Jansen R, etal |title=Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation. |journal=J. Clin. Invest. |volume=87 |issue= 1 |pages= 203–7 |year= 1991 |pmid= 1670635 |doi=10.1172/JCI114972 | pmc=295026  }}
* {{cite journal | vauthors = Fenton WA, Hack AM, Kraus JP, Rosenberg LE | title = Immunochemical studies of fibroblasts from patients with methylmalonyl-CoA mutase apoenzyme deficiency: detection of a mutation interfering with mitochondrial import | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 5 | pages = 1421–4 | date = March 1987 | pmid = 2881300 | pmc = 304442 | doi = 10.1073/pnas.84.5.1421 }}
*{{cite journal |vauthors=Jansen R, Ledley FD |title=Heterozygous mutations at the mut locus in fibroblasts with mut0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning. |journal=Am. J. Hum. Genet. |volume=47 |issue= 5 |pages= 808–14 |year= 1990 |pmid= 1977311 |doi= | pmc=1683687 }}
* {{cite journal | vauthors = Zoghbi HY, O'Brien WE, Ledley FD | title = Linkage relationships of the human methylmalonyl CoA mutase to the HLA and D6S4 loci on chromosome 6 | journal = Genomics | volume = 3 | issue = 4 | pages = 396–8 | date = November 1988 | pmid = 2907507 | doi = 10.1016/0888-7543(88)90135-8 }}
*{{cite journal |vauthors=Nham SU, Wilkemeyer MF, Ledley FD |title=Structure of the human methylmalonyl-CoA mutase (MUT) locus. |journal=Genomics |volume=8 |issue= 4 |pages= 710–6 |year= 1991 |pmid= 1980486 |doi=10.1016/0888-7543(90)90259-W }}
* {{cite journal | vauthors = Kolhouse JF, Utley C, Allen RH | title = Isolation and characterization of methylmalonyl-CoA mutase from human placenta | journal = The Journal of Biological Chemistry | volume = 255 | issue = 7 | pages = 2708–12 | date = April 1980 | pmid = 6102092 | doi =  }}
*{{cite journal   |vauthors=Ledley FD, Lumetta M, Nguyen PN, etal |title=Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 10 |pages= 3518–21 |year= 1988 |pmid= 2453061 |doi=10.1073/pnas.85.10.3518 | pmc=280243  }}
* {{cite journal | vauthors = Fenton WA, Hack AM, Willard HF, Gertler A, Rosenberg LE | title = Purification and properties of methylmalonyl coenzyme A mutase from human liver | journal = Archives of Biochemistry and Biophysics | volume = 214 | issue = 2 | pages = 815–23 | date = April 1982 | pmid = 6124211 | doi = 10.1016/0003-9861(82)90088-1 }}
*{{cite journal   |vauthors=Jansen R, Kalousek F, Fenton WA, etal |title=Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction. |journal=Genomics |volume=4 |issue= 2 |pages= 198–205 |year= 1989 |pmid= 2567699 |doi=10.1016/0888-7543(89)90300-5 }}
* {{cite journal | vauthors = Qureshi AA, Crane AM, Matiaszuk NV, Rezvani I, Ledley FD, Rosenblatt DS | title = Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria | journal = The Journal of Clinical Investigation | volume = 93 | issue = 4 | pages = 1812–9 | date = April 1994 | pmid = 7909321 | pmc = 294249 | doi = 10.1172/JCI117166 }}
*{{cite journal |vauthors=Fenton WA, Hack AM, Kraus JP, Rosenberg LE |title=Immunochemical studies of fibroblasts from patients with methylmalonyl-CoA mutase apoenzyme deficiency: detection of a mutation interfering with mitochondrial import. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 5 |pages= 1421–4 |year= 1987 |pmid= 2881300 |doi=10.1073/pnas.84.5.1421 | pmc=304442  }}
* {{cite journal | vauthors = Crane AM, Ledley FD | title = Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia | journal = American Journal of Human Genetics | volume = 55 | issue = 1 | pages = 42–50 | date = July 1994 | pmid = 7912889 | pmc = 1918235 | doi =  }}
*{{cite journal |vauthors=Zoghbi HY, O'Brien WE, Ledley FD |title=Linkage relationships of the human methylmalonyl CoA mutase to the HLA and D6S4 loci on chromosome 6. |journal=Genomics |volume=3 |issue= 4 |pages= 396–8 |year= 1989 |pmid= 2907507 |doi=10.1016/0888-7543(88)90135-8 }}
* {{cite journal | vauthors = Janata J, Kogekar N, Fenton WA | title = Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation | journal = Human Molecular Genetics | volume = 6 | issue = 9 | pages = 1457–64 | date = September 1997 | pmid = 9285782 | doi = 10.1093/hmg/6.9.1457 }}
*{{cite journal |vauthors=Kolhouse JF, Utley C, Allen RH |title=Isolation and characterization of methylmalonyl-CoA mutase from human placenta. |journal=J. Biol. Chem. |volume=255 |issue= 7 |pages= 2708–12 |year= 1980 |pmid= 6102092 |doi=  }}
*{{cite journal   |vauthors=Fenton WA, Hack AM, Willard HF, etal |title=Purification and properties of methylmalonyl coenzyme A mutase from human liver. |journal=Arch. Biochem. Biophys. |volume=214 |issue= 2 |pages= 815–23 |year= 1982 |pmid= 6124211 |doi=10.1016/0003-9861(82)90088-1 }}
*{{cite journal   |vauthors=Qureshi AA, Crane AM, Matiaszuk NV, etal |title=Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria. |journal=J. Clin. Invest. |volume=93 |issue= 4 |pages= 1812–9 |year= 1994 |pmid= 7909321 |doi=10.1172/JCI117166 | pmc=294249  }}
*{{cite journal |vauthors=Crane AM, Ledley FD |title=Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia. |journal=Am. J. Hum. Genet. |volume=55 |issue= 1 |pages= 42–50 |year= 1994 |pmid= 7912889 |doi= | pmc=1918235 }}
*{{cite journal |vauthors=Janata J, Kogekar N, Fenton WA |title=Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation. |journal=Hum. Mol. Genet. |volume=6 |issue= 9 |pages= 1457–64 |year= 1998 |pmid= 9285782 |doi=10.1093/hmg/6.9.1457 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mma  GeneReviews/NIH/NCBI/UW entry on Methylmalonic Acidemia]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mma  GeneReviews/NIH/NCBI/UW entry on Methylmalonic Acidemia]
* {{MeshName|Methylmalonyl-CoA+Mutase}}
* {{MeshName|Methylmalonyl-CoA+Mutase}}
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[[Category:Human proteins]]
[[Category:Human proteins]]
[[Category:EC 5.4.99]]
[[Category:EC 5.4.99]]

Latest revision as of 03:28, 10 April 2018

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methylmalonyl-CoA mutase
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EC number5.4.99.2
CAS number9023-90-9
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Methylmalonyl-CoA mutase (MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.[1]

MCM was first identified in rat liver and sheep kidney in 1955. In its latent form, it is 750 amino acids in length. Upon entry to the mitochondria, the 32 amino acid mitochondrial leader sequence at the N-terminus of the protein is cleaved, forming the fully processed monomer. The monomers then associate into homodimers, and bind AdoCbl (one for each monomer active site) to form the final, active holoenzyme form.[2]

Structure

Gene

The MUT gene lies on the chromosome location of 6p12.3 and consists of 13 exons, spanning over 35kb.[3]

Protein

The mature enzyme is a homodimer with the N-terminal CoA binding domain and the C- terminal cobalamin-binding domain.[4]

Function

Methylmalonyl-CoA mutase is expressed in high concentrations in the kidney, in intermediate concentrations in the heart, ovaries, brain, muscle, and liver, and in low concentrations in the spleen.[2] The enzyme can be found all throughout the central nervous system (CNS).[2] MCM resides in the mitochondria, where a number of substances, including the branched-chain amino acids isoleucine and valine, as well as methionine, threonine, thymine and odd-chain fatty acids, are metabolized via methylmalonate semialdehyde (MMlSA) or propionyl-CoA (Pr-CoA) to a common compound - methylmalonyl-CoA (MMl-CoA). MCM catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA, requiring cobalamin (vitamin B12) in the form of adenosylcobalamin (AdoCbl) as a cofactor. As an important step in propionate catabolism, this reaction is required for the degradation of odd-chain fatty acids, the amino acids valine, isoleucine, methionine, and threonine, and cholesterol,[5] funneling metabolites from the breakdown of these amino acids into the tricarboxylic acid cycle.[6]

Methylmalonyl-CoA mutase catalyzes the following reaction:

L-methylmalonyl-CoA methylmalonyl-CoA mutase Succinyl-CoA
File:L-methylmalonyl-CoA.png  
File:Biochem reaction arrow reversible NNNN horiz med.svg
 
  methylmalonyl-CoA mutase


The substrate of methylmalonyl-CoA mutase, methylmalonyl-CoA, is primarily derived from propionyl-CoA, a substance formed from the catabolism and digestion of isoleucine, valine, threonine, methionine, thymine, cholesterol, or odd-chain fatty acids.The product of the enzyme, succinyl-CoA, is a key molecule of the TCA cycle.

Clinical significance

A deficiency of this enzyme is responsible for an inherited disorder of metabolism, Methylmalonyl-CoA mutase deficiency, which is one of the causes of methylmalonic acidemia (also referred to as methylmalonic aciduria or MMA). MMA is an autosomal recessive inherited inborn error of metabolism, characterized by recurrent episodes of vomiting, lethargy, profound ketoacidosis, hyperammonemia, and pancytopenia in infancy, and may cause early death. Complications include cardiomyopathy, metabolic stroke, pancreatitis, and progressive renal failure.[1][7]

Either mutations to the gene MUT (encodes methylmalonyl-CoA mutase), or MMAA (encodes a chaperone protein of methylmalonyl-CoA mutase, MMAA protein) can lead to methylmalonyl acidemia.[8] Mutations to MUT can be categorized as either MUT0 (demonstrates no activity even in presence of excess AdoCbl), or MUT1 (demonstrates very low activity in presence of excess AdoCbl).[9] Over half of the mutations of MUT are missense mutations[10] while nonsense mutations comprise a significant remaining fraction (approximately 14%)[11]

Common treatment methods for MMA include a liver transplant or a liver and kidney transplant to combat the renal disease of methylmalonic acidemia. However, detrimental neurological effects can continue to plague patients even after a successful operation. It is thought that this is due to the widespread presence of methylmalonyl-CoA mutase throughout the central nervous system. Due to the loss of functionality of the enzyme, substrate levels build up in the CNS. The substrate, L-methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid that, due to the poor dicarboxylic acid transport capacities of the blood-brain barrier, is effectively trapped within the CNS, leading to neurological debilitation. To combat these effects perioperative anti-catabolic regimes and no diet discontinuation are recommended.[2]

MUT has also been linked to bovine tuberculosis (bTB), a form of tuberculosis that affects mostly livestock and accounts for 10% of human cases.[12][unreliable medical source?] It has been proposed that high MUT expression (thus high methylmalonyl-CoA mutase levels) leads to lower cholesterol levels which increases resistance to bTB and affords an improved response to the BCG vaccine.[12][unreliable medical source?]

The murine model has proven an adequate and accurate way of studying the effects of MMA, and potential treatment methods.[13][14]

Mechanism

File:MUT.png
MCM's reaction mechanism

The MCM reaction mechanism begins with homolytic cleavage of AdoB12's C-Co(III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. The Co ion, therefore, fluctuates between its Co(III) and Co(II) oxidation states [the two states are spectroscopically distinguishable: Co(III) is red and diamagnetic (no unpaired electrons), whereas Co(II) is yellow and paramagnetic (unpaired electrons)]. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible generator of a free radical. The C-Co(III) bond is weak, with a dissociation energy = 109 kJ/mol, and appears to be further weakened through steric interactions with the enzyme. The homolytic reaction is unusual in biology, as is the presence of a metal-carbon bond.

Methylmalonyl-CoA mutase is a member of the isomerase subfamily of adenosylcobalamin-dependent enzymes. Furthermore, it is classified as class I, as it is a ‘DMB-off’/’His-on’ enzyme. This refers to the nature of the AdoCbl cofactor in the active site of methylmalonyl CoA.[15] AdoCbl is composed of a central cobalt-containing corrin ring, an upper axial ligand (β-axial ligand), and a lower axial ligand (α-axial ligand). In methylmalonyl-CoA mutase, the β-axial ligand 5’-deoxy-5’-adenosine reversibly dissociated to give the deoxyadenosyl radical. The α-axial ligand 5,6-dimethylbenzimidazole (DMB) is involved in organizing the active site to enable histidine-610 to bond with Co, instead of DMB (the reason for the ‘DMB-off’/’His-on’ notation).[15] Binding of histidine-610 residue increases the rate of homolytic β-axial ligand – Co bond breakage by a factor of 1012.[16]

File:Active site MCM colors.png
MCM active site. Corrin ring and α-axial ligand (DMB): (yellow), β-axial ligand: (green), substrate/product: (cyan), residues interacting with β-axial ligand: glu370, asn366, gly91, ala139 (blue), residues interacting with substrate: gln197, his244, arg207, tyr89 (red), and his610: (orange).[17] Rendered from PDB 4REQ.[18]

Other important residues of methylmalonyl-CoA mutase include Histidine-244, which acts as a general acid near the substrate and shields the radical species from side reactions involving oxygen,[19] Glutamate-370, whose hydrogen bond with the 2’-OH group of the ribose of the β-axial ligand forces interaction between the β-axial ligand radical species and the substrate,[20] and tyrosine-89 which stabilizes reactive radical intermediates and accounts for the stereo-selectivity of the enzyme.[17][21]

The processing protein, MMAA protein, fills the important role of aiding cofactor loading and exchange.[8][22] MMAA protein favors association with the MCM apoenzyme, and allows for the transfer of the AdoCbl cofactor to the enzyme active site.[22] Furthermore, if the bound AdoCbl accrues oxidative damage during normal functioning, MMAA protein fosters exchange of the damaged cofactor for a new AdoCbl via a GTP-reliant pathway.[8][22]

Interactions

References

  1. ↑ 1.0 1.1 Keyfi F, Sankian M, Moghaddassian M, Rolfs A, Varasteh AR (January 2016). "Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency". Gene. 576 (1 Pt 2): 208–13. doi:10.1016/j.gene.2015.10.002. PMID 26449400.
  2. ↑ 2.0 2.1 2.2 2.3 Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O (December 2009). "Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain". Neuroscience. 164 (2): 578–87. doi:10.1016/j.neuroscience.2009.08.028. PMID 19699272.
  3. ↑ Chandler RJ, Venditti CP (2016-10-01). "Genetic and genomic systems to study methylmalonic acidemia". Molecular Genetics and Metabolism. 86 (1–2): 34–43. doi:10.1016/j.ymgme.2005.07.020. PMC 2657357. PMID 16182581.
  4. ↑ Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML (May 1996). "Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5550–5. doi:10.1073/pnas.93.11.5550. PMC 39284. PMID 8643613.
  5. ↑ Martínez MA, Rincón A, Desviat LR, Merinero B, Ugarte M, Pérez B (April 2005). "Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants". Molecular Genetics and Metabolism. 84 (4): 317–25. doi:10.1016/j.ymgme.2004.11.011. PMID 15781192.
  6. ↑ Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR (December 2014). "Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency". Human Mutation. 35 (12): 1449–58. doi:10.1002/humu.22633. PMC 4441004. PMID 25125334.
  7. ↑ Dündar H, Özgül RK, Güzel-Ozantürk A, Dursun A, Sivri S, Aliefendioğlu D, Coşkun T, Tokatli A (August 2012). "Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations". Molecular Genetics and Metabolism. 106 (4): 419–23. doi:10.1016/j.ymgme.2012.05.014. PMID 22727635.
  8. ↑ 8.0 8.1 8.2 Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME (January 2011). "Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein". Biochemical and Biophysical Research Communications. 404 (1): 443–7. doi:10.1016/j.bbrc.2010.11.141. PMID 21138732.
  9. ↑ Drennan CL, Matthews RG, Rosenblatt DS, Ledley FD, Fenton WA, Ludwig ML (May 1996). "Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5550–5. doi:10.1073/pnas.93.11.5550. PMC 39284. PMID 8643613.
  10. ↑ Forny P, Froese DS, Suormala T, Yue WW, Baumgartner MR (December 2014). "Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency". Human Mutation. 35 (12): 1449–58. doi:10.1002/humu.22633. PMC 4441004. PMID 25125334.
  11. ↑ Buck NE, Wood LR, Hamilton NJ, Bennett MJ, Peters HL (November 2012). "Treatment of a methylmalonyl-CoA mutase stopcodon mutation". Biochemical and Biophysical Research Communications. 427 (4): 753–7. doi:10.1016/j.bbrc.2012.09.133. PMID 23041189.
  12. ↑ 12.0 12.1 de la Fuente J, Gortazar C, Vicente J, Villar M (March 2011). "Host expression of methylmalonyl-CoA mutase and tuberculosis: a missing link?". Medical Hypotheses. 76 (3): 361–4. doi:10.1016/j.mehy.2010.10.040. PMID 21084167.
  13. ↑ Chandler RJ, Venditti CP (November 2012). "Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA)". Molecular Genetics and Metabolism. 107 (3): 617–9. doi:10.1016/j.ymgme.2012.09.019. PMC 3522145. PMID 23046887.
  14. ↑ Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP (August 2013). "Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia". Proceedings of the National Academy of Sciences of the United States of America. 110 (33): 13552–7. doi:10.1073/pnas.1302764110. PMC 3746875. PMID 23898205.
  15. ↑ 15.0 15.1 Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (June 2012). "Role of vitamin B12 on methylmalonyl-CoA mutase activity". Journal of Zhejiang University. Science. B. 13 (6): 423–37. doi:10.1631/jzus.B1100329. PMC 3370288. PMID 22661206.
  16. ↑ Vlasie M, Chowdhury S, Banerjee R (May 2002). "Importance of the histidine ligand to coenzyme B12 in the reaction catalyzed by methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 277 (21): 18523–7. doi:10.1074/jbc.M111809200. PMID 11893736.
  17. ↑ 17.0 17.1 Mancia F, Smith GA, Evans PR (June 1999). "Crystal structure of substrate complexes of methylmalonyl-CoA mutase". Biochemistry. 38 (25): 7999–8005. doi:10.1021/bi9903852. PMID 10387043.
  18. ↑ Mancia F, Evans PR (June 1998). "Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism". Structure. 6 (6): 711–20. doi:10.1016/s0969-2126(98)00073-2. PMID 9655823.
  19. ↑ Maiti N, Widjaja L, Banerjee R (November 1999). "Proton transfer from histidine 244 may facilitate the 1,2 rearrangement reaction in coenzyme B(12)-dependent methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 274 (46): 32733–7. doi:10.1074/jbc.274.46.32733. PMID 10551831.
  20. ↑ Buckel W, Friedrich P, Golding BT (October 2012). "Hydrogen bonds guide the short-lived 5'-deoxyadenosyl radical to the place of action". Angewandte Chemie. 51 (40): 9974–6. doi:10.1002/anie.201205299. PMID 22945861.
  21. ↑ Thomä NH, Meier TW, Evans PR, Leadlay PF (October 1998). "Stabilization of radical intermediates by an active-site tyrosine residue in methylmalonyl-CoA mutase". Biochemistry. 37 (41): 14386–93. doi:10.1021/bi981375o. PMID 9772164.
  22. ↑ 22.0 22.1 22.2 Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW (December 2010). "Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation". The Journal of Biological Chemistry. 285 (49): 38204–13. doi:10.1074/jbc.M110.177717. PMC 2992254. PMID 20876572.
  23. ↑ 23.0 23.1 Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW (December 2010). "Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation". The Journal of Biological Chemistry. 285 (49): 38204–13. doi:10.1074/jbc.M110.177717. PMC 2992254. PMID 20876572.
  24. ↑ Padovani D, Labunska T, Banerjee R (June 2006). "Energetics of interaction between the G-protein chaperone, MeaB, and B12-dependent methylmalonyl-CoA mutase". The Journal of Biological Chemistry. 281 (26): 17838–44. doi:10.1074/jbc.M600047200. PMID 16641088.
  25. ↑ Taoka S, Padmakumar R, Lai MT, Liu HW, Banerjee R (December 1994). "Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters". The Journal of Biological Chemistry. 269 (50): 31630–4. PMID 7989334.

Further reading

External links

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