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{{Protein
{{infobox enzyme
   |Name=Liver arginase
| Name = Arginase
   |image=Fullsize.jpg
| EC_number = 3.5.3.1
   |caption=Arginase{{PDB|1CEV}}.
| CAS_number = 9000-96-8
   |Symbol=ARG1  
| IUBMB_EC_number = 3/5/3/1
| GO_code = 0004053
| image = 2pha humanarginase.png
| width =
| caption = Ribbon diagram of human arginase I trimer. PDB entry {{PDBe|2pha}}<ref name="pmid17469833">{{cite journal | vauthors = Di Costanzo L, Pique ME, Christianson DW | title = Crystal structure of human arginase I complexed with thiosemicarbazide reveals an unusual thiocarbonyl mu-sulfide ligand in the binuclear manganese cluster | journal = J. Am. Chem. Soc. | volume = 129 | issue = 20 | pages = 6388–9 |date=May 2007 | pmid = 17469833 | pmc = 2593847 | doi = 10.1021/ja071567j }}</ref>
}}
{{Infobox protein
   |Name=[[ARG1|Liver arginase]]
   |image= 1hq5.jpg
   |caption=
   |Symbol=[[ARG1]]
   |AltSymbols=
   |AltSymbols=
   |HGNCid=663
   |HGNCid=663
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   |PDB=
   |PDB=
}}
}}
{{Protein
{{Infobox protein
   |Name=Arginase, type II
   |Name=[[ARG2|Arginase, type II]]
   |image=
   |image=
   |caption=
   |caption=
   |Symbol=ARG2  
   |Symbol=[[ARG2]]
   |AltSymbols=
   |AltSymbols=
   |HGNCid=664
   |HGNCid=664
Line 35: Line 45:
   |PDB=
   |PDB=
}}
}}
'''Arginase''' is a [[manganese]]-containing [[enzyme]]. The reaction catalyzed by this enzyme is: [[arginine]] + [[Water|H<sub>2</sub>O]] → [[ornithine]] + [[urea]]. It is the final [[enzyme]] of the [[urea cycle]].
'''Arginase''' ({{EC number|3.5.3.1}}, ''arginine amidinase'', ''canavanase'', ''L-arginase'', ''arginine transamidinase'') is a [[manganese]]-containing [[enzyme]]. The reaction catalyzed by this enzyme is: [[arginine]] + [[Water|H<sub>2</sub>O]] → [[ornithine]] + [[urea]]. It is the final [[enzyme]] of the [[urea cycle]]. It is ubiquitous to all domains of life.
 
== Structure and function ==
Arginase belong to the [[ureohydrolase]] family of enzymes.
 
Arginase catalyzes the fifth and final step in the [[urea cycle]], a series of biochemical reactions in mammals during which the body disposes of harmful [[ammonia]]. Specifically, arginase converts L-[[arginine]] into L-[[ornithine]] and urea.<ref name="pmid9806879">{{cite journal | vauthors = Wu G, Morris SM | title = Arginine metabolism: nitric oxide and beyond | journal = The Biochemical Journal | volume = ( Pt 1) | issue = | pages = 1–17 |date=November 1998 | series = 336  | pmid = 9806879 | pmc = 1219836 | doi = | url = http://www.biochemj.org/bj/336/0001/bj3360001.htm }}</ref> Mammalian arginase is active as a trimer, but some bacterial arginases are hexameric.<ref name="pmid18360740">{{cite journal | vauthors = Dowling DP, Di Costanzo L, Gennadios HA, Christianson DW | title = Evolution of the arginase fold and functional diversity | journal = Cell. Mol. Life Sci. | volume = 65 | issue = 13 | pages = 2039–55 |date=July 2008 | pmid = 18360740 | pmc = 2653620 | doi = 10.1007/s00018-008-7554-z }}</ref> The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn<sup>2+</sup> [[ions]] coordinate with water, orienting and stabilizing the molecule and allowing water to act as a [[nucleophile]] and attack L-arginine, hydrolyzing it into ornithine and urea.<ref name="pmid17562323"/>


==Structure and Function of Arginase==
In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of the liver. The second isozyme, Arginase II, has been implicated in the regulation of the arginine/ornithine concentrations in the cell. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain.<ref name="pmid12055339">{{cite journal | author = Morris SM | title = Regulation of enzymes of the urea cycle and arginine metabolism | journal = Annual Review of Nutrition | volume = 22 | issue = 1| pages = 87–105 | year = 2002 | pmid = 12055339 | doi = 10.1146/annurev.nutr.22.110801.140547 | url = | issn = }}</ref> The second isozyme may be found in the absence of other urea cycle enzymes.<ref name="pmid17562323">{{cite journal | vauthors = Di Costanzo L, Moulin M, Haertlein M, Meilleur F, Christianson DW | title = Expression, purification, assay, and crystal structure of perdeuterated human arginase I | journal = Archives of Biochemistry and Biophysics | volume = 465 | issue = 1 | pages = 82–9 |date=September 2007 | pmid = 17562323 | pmc = 2018606 | doi = 10.1016/j.abb.2007.04.036 }}</ref>
'''Arginase''' is the fifth and final step in the [[urea cycle]], a series of biophysical reactions in mammals during which the body disposes of harmful [[ammonia]]. Specifically, arginase converts L-[[arginine]] into L-[[ornithine]] and urea. <ref>Wu, G.; Morris, S.M., Jr. Arginine Metabolism: Nitric Oxide and Beyond. ''Biochem. J.'' 1998, 336, 1-17 </ref> In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of the liver. The second isozyme, Arginase II, has been implicated in the regulation of the arginine/ornithene concentrations in the cell. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain<ref>Morris, S.M., Jr. Regulation of Enzymes in the Urea Cycle and Arginine Metabolism.''Annu. Rev. Nutr.'' 2002, 22, 87-105 2</ref>. The second isozyme may be found in the absence of other urea cycle enzymes<ref>Di Costanzo, L., Moulin, Martine; Haertlein, Michael; Meilleur, Flora; Christianson, D. Expression, purification, assay, and crystal structure of perdeuterated human arginase I. ''Archives of Biochemistry and Biophysics.'' 2007, 465, 82-89.</ref>.
Arginase consists of three tetramers. The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. these Mn<sup>2+</sup> [[ions]] coordinate with water, orientating and stabilizing the molecule and allowing water to act as a [[nucleophile]] and attack L-arginine, hydrolyzing it into ornithene and urea<ref>Di Costanzo, L., Moulin, Martine; Haertlein, Michael; Meilleur, Flora; Christianson, D. Expression, purification, assay, and crystal structure of perdeuterated human arginase I. ''Archives of Biochemistry and Biophysics.'' 2007, 465, 82-89.</ref>.
==Mechanism==
The active site holds L-arginine in place via hydrogen bonding between the guanidinium group with Glu227. This bonding orients L-arginine for nucleophillic attack by the metal-associated hydroxide ion at the guanidinium group. This results in a tetrahedral intermediate. The manganese ions act to stabilize both the hydroxyl troup in the tetrahedral intermediate, as well as the developing sp<small>3</small> lone electron pair on the NH<sub>2</sub> group as the tetrahedral intermediate is formed.<ref>Reczkowski R. S., Ash D. E. Rat Liver Arginase: kinetic mechanism, alternate substrates, and inhibitors. ''Archives of Biochemistry and Biophysics.'' 1994, 312, 31-37. </ref>


[[Image:Arginase1.gif|none]]
== Mechanism ==


[[Image:Arginase.jpeg|thumb|600px|Tetrahedral intermediate with boronic acid inhibitor ABH]]
The active site holds L-arginine in place via hydrogen bonding between the guanidine chloride group with Glu227. This bonding orients L-arginine for nucleophilic attack by the metal-associated hydroxide ion at the guanidine chloride group. This results in a tetrahedral intermediate. The manganese ions act to stabilize both the hydroxyl group in the tetrahedral intermediate, as well as the developing sp<small>3</small> lone electron pair on the NH<sub>2</sub> group as the tetrahedral intermediate is formed.<ref name="pmid8031143">{{cite journal | vauthors = Reczkowski RS, Ash DE | title = Rat liver arginase: kinetic mechanism, alternate substrates, and inhibitors | journal = Archives of Biochemistry and Biophysics | volume = 312 | issue = 1 | pages = 31–7 |date=July 1994 | pmid = 8031143 | doi = 10.1006/abbi.1994.1276 | url = | issn = }}</ref>
<!-- Deleted image removed: [[Image:Arginase1.gif|none|{{deletable image-caption|1=Wednesday, 24 June 2009}}]] -->
<!--Deleted image removed: [[Image:Arginase.jpeg|thumb|600px|{{Tetrahedral intermediate with boronic acid inhibitor ABH]]=Wednesday, 28 September 2011}}]]-->


Arginase's active site is extraordinarily specific. Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate  group and all three positions on the alpha amino group. N-hyroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.<ref>Reczkowski R. S., Ash D. E. Rat Liver Arginase: kinetic mechanism, alternate substrates, and inhibitors. ''Archives of Biochemistry and Biophysics.'' 1994, 312, 31-37. </ref>
Arginase's active site is extraordinarily specific.{{citation needed|date=July 2017}} Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate  group and all three positions on the alpha amino group. N-hydroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.<ref name="pmid8031143"/>
Additionally, 2(S)-aminio=6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.<ref>Cox, J.; Kim, N; Traish, A.; Christianson, D. Arginase−boronic acid complex highlights a physiological role in erectile function. ''Nature Structural Biology.'' 1999, 6, 1043-1047.</ref>


==Role in Sexual Response==
Additionally, 2(S)-amino-6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.<ref name="pmid10542097">{{cite journal | vauthors = Cox JD, Kim NN, Traish AM, Christianson DW | title = Arginase-boronic acid complex highlights a physiological role in erectile function | journal = Nature Structural Biology | volume = 6 | issue = 11 | pages = 1043–7 |date=November 1999 | pmid = 10542097 | doi = 10.1038/14929 | url = | issn = }}</ref>
Arginase II is coexpressed with NO synthase in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to nitric oxide (NO) synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.<ref>Cama, E.; Colleluori, D. M.; Emig, F. A.; Shin, H.; Kim, S. W.; Kim, N. N.; Traish, A. M.; Ash, D. E.; Christianson, D. W. Human Arginase II: Crystal Structure and Physiological Role in Male and Female Sexual Arousal. Biochemistry 2003, 42, 8445-8451.</ref>  


Recent studies have implicated arginase as a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme<ref>Moody, J. A.; Vernet, D.; Laidlaw, S.; Rajfer, J.; Gonzalez-Cadavid, N. F. Effects of Long-Term Oral Administration of L-Arginine on the Rat Erectile Response. J. Urol. 1997, 158, 942-947.</ref>.
== Role in sexual response ==


==Pathology==
Arginase II is coexpressed with [[Nitric oxide synthase|nitric oxide (NO) synthase]] in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to NO synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.<ref name="pmid12859189">{{cite journal | vauthors = Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW | title = Human arginase II: crystal structure and physiological role in male and female sexual arousal | journal = Biochemistry | volume = 42 | issue = 28 | pages = 8445–51 |date=July 2003 | pmid = 12859189 | doi = 10.1021/bi034340j | url = | issn = }}</ref>
Arginase deficiency typically refers to decreased function of arginase I, the liver isoform of arginase. This devidiency is commonly referred to as hyperargininemia or [[arginemia]]. The disorder is hereditary and autosomal recessive, meaning it is not sex-linked, and two copies of the mutated gene must be inherited in order for the disorder to be inherited. It is characterized by lowered activity of arginase in hepatic cells. Additionally, the disorder is considered to be the rarest of the heritable defects in ureagenesis. Unlike other urea cycle disorders, ureagenesis still persists in subjects with arginase deficiency. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginase triggers increased expression of arginase II. The enzymes in the kidney will then partially catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess [[arginine]] and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.<ref>Iyer, R.; Yoo, P.; Kern, R.; Rozengurt, N.; Tsoa, R.; O'Brien, W.; Yu, H.; Grody, W. Mouse Model for Human Arginase Deficiency. Mol. and Cell Bio. 2002, 22:4491-4498.</ref>.


Symptoms of the disorder include neurological impairmentdementia, retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and pharmaceutical developments, no cure or completely effective therapy currently exists<ref>Iyer, R.; Yoo, P.; Kern, R.; Rozengurt, N.; Tsoa, R.; O'Brien, W.; Yu, H.; Grody, W. Mouse Model for Human Arginase Deficiency. Mol. and Cell Bio. 2002, 22:4491-4498. </ref>.
Arginase is a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme.<ref name="pmid9258123">{{cite journal | vauthors = Moody JA, Vernet D, Laidlaw S, Rajfer J, Gonzalez-Cadavid NF | title = Effects of long-term oral administration of L-arginine on the rat erectile response | journal = The Journal of Urology | volume = 158 | issue = 3 Pt 1 | pages = 942–7 |date=September 1997 | pmid = 9258123 | doi = 10.1016/S0022-5347(01)64368-4 | url = | issn = }}</ref>


== Pathology ==


{{reflist|2}}{{/reflist}}
Arginase [[Deficiency (medicine)|deficiency]] typically refers to decreased function of arginase I, the liver isoform of arginase. This deficiency is commonly referred to as hyperargininemia or [[arginemia]]. The disorder is hereditary and [[autosomal]] recessive. It is characterized by lowered activity of arginase in [[hepatic cells]]. It is considered to be the rarest of the heritable defects in [[ureagenesis]]. Arginase deficiency, unlike other urea cycle disorders, does not entirely prevent ureagenesis. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginine triggers increased expression of arginase II. The enzymes in the kidney will then catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess [[arginine]] and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.<ref name="pmid12052859">{{cite journal | vauthors = Iyer RK, Yoo PK, Kern RM, Rozengurt N, Tsoa R, O'Brien WE, Yu H, Grody WW, Cederbaum SD | title = Mouse model for human arginase deficiency | journal = Molecular and Cellular Biology | volume = 22 | issue = 13 | pages = 4491–8 |date=July 2002 | pmid = 12052859 | pmc = 133904 | doi = 10.1128/MCB.22.13.4491-4498.2002 | url =  | issn = }}</ref>


==External links==
Symptoms of the [[Genetic disorder|disorder]] include neurological impairment, [[dementia]], retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and [[pharmaceutical]] developments, no cure or completely effective therapy currently exists.<ref name="pmid12052859"/>
* {{MeshName|Arginase}}
 
== Animal studies ==
 
Arginase1 is activated by lactic acid in tumors to stimulate macrophages to help a tumor grow. When arginase1 was inhibited in a mouse model tumor size was greatly reduced.<ref name="pmid25043024">{{cite journal | vauthors = Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R | title = Functional polarization of tumour-associated macrophages by tumour-derived lactic acid | journal = Nature | volume = 513 | issue = 7519 | pages = 559–63 | year = 2014 | pmid = 25043024 | pmc = 4301845 | doi = 10.1038/nature13490 }}</ref>


[[Category:EC 3.5.3]]
Arginase has been studied, ''in vitro'', to treat several types of [[cancer]], such as: breast, rectal, and colon. Arginase is used to decrease the [[arginine]] levels in blood serum in order to starve the cancer cells that are [[auxotrophy|auxotrophic]] to arginine [[aminoacid]]. The ''in vivo'' approach revealed some problems that were overcame through some modifications that are described in several patent process, namely [[pegylation]].<ref>{{cite journal | vauthors = Fernandes HS, Teixeira CS, Fernandes PA, Ramos MJ, Cerqueira NM | title = Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections | journal = Expert Opinion on Therapeutic Patents | volume =  | issue =  | date = November 2016 | pmid = 27813440 | doi = 10.1080/13543776.2017.1254194 | pages=1–15}}</ref>


[[pl:Arginaza]]
== References ==
[[zh:精氨酸酶]]
{{Reflist|2}}


== External links ==
* {{MeshName|Arginase}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=arg1  GeneReviews/NIH/NCBI/UW entry on Arginase Deficiency]
* [http://www.expasy.org/prosite/PDOC00135 Arginase family signature and profile] in [[PROSITE]]


{{hydrolase-stub}}
{{Urea cycle enzymes}}
{{Urea cycle enzymes}}
{{Carbon-nitrogen non-peptide hydrolases}}
{{Carbon-nitrogen non-peptide hydrolases}}
{{Enzymes}}
{{Nitric oxide signaling}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
[[Category:EC 3.5.3]]
[[Category:Urea cycle]]

Revision as of 20:14, 28 October 2017

Arginase
File:2pha humanarginase.png
Ribbon diagram of human arginase I trimer. PDB entry 2pha[1]
Identifiers
EC number3.5.3.1
CAS number9000-96-8
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Liver arginase
File:1hq5.jpg
Identifiers
SymbolARG1
Entrez383
HUGO663
OMIM608313
RefSeqNM_000045
UniProtP05089
Other data
EC number3.5.3.1
LocusChr. 6 q23
Arginase, type II
Identifiers
SymbolARG2
Entrez384
HUGO664
OMIM107830
RefSeqNM_001172
UniProtP78540
Other data
EC number3.5.3.1
LocusChr. 14 q24.1

Arginase (EC 3.5.3.1, arginine amidinase, canavanase, L-arginase, arginine transamidinase) is a manganese-containing enzyme. The reaction catalyzed by this enzyme is: arginine + H2O → ornithine + urea. It is the final enzyme of the urea cycle. It is ubiquitous to all domains of life.

Structure and function

Arginase belong to the ureohydrolase family of enzymes.

Arginase catalyzes the fifth and final step in the urea cycle, a series of biochemical reactions in mammals during which the body disposes of harmful ammonia. Specifically, arginase converts L-arginine into L-ornithine and urea.[2] Mammalian arginase is active as a trimer, but some bacterial arginases are hexameric.[3] The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orienting and stabilizing the molecule and allowing water to act as a nucleophile and attack L-arginine, hydrolyzing it into ornithine and urea.[4]

In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of the liver. The second isozyme, Arginase II, has been implicated in the regulation of the arginine/ornithine concentrations in the cell. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain.[5] The second isozyme may be found in the absence of other urea cycle enzymes.[4]

Mechanism

The active site holds L-arginine in place via hydrogen bonding between the guanidine chloride group with Glu227. This bonding orients L-arginine for nucleophilic attack by the metal-associated hydroxide ion at the guanidine chloride group. This results in a tetrahedral intermediate. The manganese ions act to stabilize both the hydroxyl group in the tetrahedral intermediate, as well as the developing sp3 lone electron pair on the NH2 group as the tetrahedral intermediate is formed.[6]

Arginase's active site is extraordinarily specific.[citation needed] Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate group and all three positions on the alpha amino group. N-hydroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.[6]

Additionally, 2(S)-amino-6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.[7]

Role in sexual response

Arginase II is coexpressed with nitric oxide (NO) synthase in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to NO synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.[8]

Arginase is a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme.[9]

Pathology

Arginase deficiency typically refers to decreased function of arginase I, the liver isoform of arginase. This deficiency is commonly referred to as hyperargininemia or arginemia. The disorder is hereditary and autosomal recessive. It is characterized by lowered activity of arginase in hepatic cells. It is considered to be the rarest of the heritable defects in ureagenesis. Arginase deficiency, unlike other urea cycle disorders, does not entirely prevent ureagenesis. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginine triggers increased expression of arginase II. The enzymes in the kidney will then catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess arginine and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.[10]

Symptoms of the disorder include neurological impairment, dementia, retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and pharmaceutical developments, no cure or completely effective therapy currently exists.[10]

Animal studies

Arginase1 is activated by lactic acid in tumors to stimulate macrophages to help a tumor grow. When arginase1 was inhibited in a mouse model tumor size was greatly reduced.[11]

Arginase has been studied, in vitro, to treat several types of cancer, such as: breast, rectal, and colon. Arginase is used to decrease the arginine levels in blood serum in order to starve the cancer cells that are auxotrophic to arginine aminoacid. The in vivo approach revealed some problems that were overcame through some modifications that are described in several patent process, namely pegylation.[12]

References

  1. ↑ Di Costanzo L, Pique ME, Christianson DW (May 2007). "Crystal structure of human arginase I complexed with thiosemicarbazide reveals an unusual thiocarbonyl mu-sulfide ligand in the binuclear manganese cluster". J. Am. Chem. Soc. 129 (20): 6388–9. doi:10.1021/ja071567j. PMC 2593847. PMID 17469833.
  2. ↑ Wu G, Morris SM (November 1998). "Arginine metabolism: nitric oxide and beyond". The Biochemical Journal. 336. ( Pt 1): 1–17. PMC 1219836. PMID 9806879.
  3. ↑ Dowling DP, Di Costanzo L, Gennadios HA, Christianson DW (July 2008). "Evolution of the arginase fold and functional diversity". Cell. Mol. Life Sci. 65 (13): 2039–55. doi:10.1007/s00018-008-7554-z. PMC 2653620. PMID 18360740.
  4. ↑ 4.0 4.1 Di Costanzo L, Moulin M, Haertlein M, Meilleur F, Christianson DW (September 2007). "Expression, purification, assay, and crystal structure of perdeuterated human arginase I". Archives of Biochemistry and Biophysics. 465 (1): 82–9. doi:10.1016/j.abb.2007.04.036. PMC 2018606. PMID 17562323.
  5. ↑ Morris SM (2002). "Regulation of enzymes of the urea cycle and arginine metabolism". Annual Review of Nutrition. 22 (1): 87–105. doi:10.1146/annurev.nutr.22.110801.140547. PMID 12055339.
  6. ↑ 6.0 6.1 Reczkowski RS, Ash DE (July 1994). "Rat liver arginase: kinetic mechanism, alternate substrates, and inhibitors". Archives of Biochemistry and Biophysics. 312 (1): 31–7. doi:10.1006/abbi.1994.1276. PMID 8031143.
  7. ↑ Cox JD, Kim NN, Traish AM, Christianson DW (November 1999). "Arginase-boronic acid complex highlights a physiological role in erectile function". Nature Structural Biology. 6 (11): 1043–7. doi:10.1038/14929. PMID 10542097.
  8. ↑ Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW (July 2003). "Human arginase II: crystal structure and physiological role in male and female sexual arousal". Biochemistry. 42 (28): 8445–51. doi:10.1021/bi034340j. PMID 12859189.
  9. ↑ Moody JA, Vernet D, Laidlaw S, Rajfer J, Gonzalez-Cadavid NF (September 1997). "Effects of long-term oral administration of L-arginine on the rat erectile response". The Journal of Urology. 158 (3 Pt 1): 942–7. doi:10.1016/S0022-5347(01)64368-4. PMID 9258123.
  10. ↑ 10.0 10.1 Iyer RK, Yoo PK, Kern RM, Rozengurt N, Tsoa R, O'Brien WE, Yu H, Grody WW, Cederbaum SD (July 2002). "Mouse model for human arginase deficiency". Molecular and Cellular Biology. 22 (13): 4491–8. doi:10.1128/MCB.22.13.4491-4498.2002. PMC 133904. PMID 12052859.
  11. ↑ Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014). "Functional polarization of tumour-associated macrophages by tumour-derived lactic acid". Nature. 513 (7519): 559–63. doi:10.1038/nature13490. PMC 4301845. PMID 25043024.
  12. ↑ Fernandes HS, Teixeira CS, Fernandes PA, Ramos MJ, Cerqueira NM (November 2016). "Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections". Expert Opinion on Therapeutic Patents: 1–15. doi:10.1080/13543776.2017.1254194. PMID 27813440.

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