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External IDsGeneCards: [1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)n/an/a
PubMed searchn/an/a
View/Edit Human
EC number2.1.2.10
CAS number37257-08-2
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Crystallographic structure of human AMT.[1]
Other data
EC number2.1.2.10
LocusChr. 3 p21.2-21.1

Aminomethyltransferase is an enzyme that catabolizes the creation of methylenetetrahydrofolate. It is part of the glycine decarboxylase complex.


The gene is about 6 kb in length and consists of nine exons. The 5′-flanking region of the gene lacks typical TATAA sequence but has a single defined transcription initiation site detected by the primer extension method. Two putative glucocorticoid-responsive elements and a putative thyroid hormone-responsive element are present. The AMT gene has been localized to 3p21.2-p21.1 by fluorescence in situ hybridization.[2] The 1209 base pair open reading frame encodes 403 amino acid precursor protein, and the deduced amino acid sequence of the mature peptide shows 90 and 68% homology to that of bovine and chicken counterpart, respectively.[3]

The protein encoded by this gene has its crystal structure resolved at 2 Angstroms. The most recent model contains two monomers related by a non-crystallographic 2-fold axis, 1176 water molecules, and 11 molecules sulfate ions in an asymmetric unit. Several dimeric interactions are observed among the residues on the N-terminal loop, on α-helix D, and the flank on either side of β-strand 8 of the two monomers.[4]


The protein encoded by AMT catalyzes the release of ammonia and the transfer of a methylene carbon unit to a tetrahydrofolate moiety. The aminomethyl intermediate is the product of the decarboxylation of glycine catalyzed by P-protein. In the reverse reaction, T-protein catalyzes the formation of the H-protein-bound aminomethyl lipoate intermediate from 5,10-CH2-H4folate, ammonia, and reduced H-protein via an ordered Ter Bi mechanism, in which reduced H-protein is the first substrate to bind followed by 5,10-CH2-H4folate and ammonia.[5][6]

Clinical significance

Mutations in the AMT gene are associated with Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), which is an inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme and, as a consequence, accumulation of large quantities of glycine in all body tissues including the brain. The majority of glycine encephalopathy presents in the neonatal period (85% as the neonatal severe form and 15% as the neonatal attenuated form). Of those presenting in infancy, 50% have the infantile attenuated form and 50% have the infantile severe form. Overall, 20% of all children presenting as either neonates or infants have a less severe outcome, defined as developmental quotient greater than 20. A minority of patients have mild or atypical forms of glycine encephalopathy.[7] The neonatal form manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have profound intellectual disability and intractable seizures. The infantile form is characterized by hypotonia, developmental delay, and seizures. The atypical forms range from milder disease, with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset. Glycine encephalopathy is suspected in individuals with elevated glycine concentration in blood and CSF. An increase in CSF glycine concentration together with an increased CSF-to-plasma glycine ratio suggests the diagnosis.[8][9] Enzymatic confirmation of the diagnosis relies on measurement of glycine cleavage system (GCS) enzyme activity in liver obtained by open biopsy or autopsy.[10][11] The majority of affected individuals have no detectable enzyme activity. The three genes in which biallelic mutations are known to cause glycine encephalopathy are: GLDC (encoding the P-protein component of the GCS complex and accounting for 70%-75% of disease), AMT (accounting for ~20% of disease), and GCSH (encoding the H-protein component of the GCS complex and accounting for <1% of disease). About 5% of individuals with enzyme-proven glycine encephalopathy do not have a mutation in any of these three genes and have a variant form of glycine encephalopathy.[12][13][14]


  1. PDB: 1WSR​; Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H (September 2005). "Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia". Journal of Molecular Biology. 351 (5): 1146–59. doi:10.1016/j.jmb.2005.06.056. PMID 16051266.
  2. Nanao, K; Takada, G; Takahashi, E; Seki, N; Komatsu, Y; Okamura-Ikeda, K; Motokawa, Y; Hayasaka, K (1 January 1994). "Structure and chromosomal localization of the aminomethyltransferase gene (AMT)". Genomics. 19 (1): 27–30. doi:10.1006/geno.1994.1007. PMID 8188235.
  3. Hayasaka, K; Nanao, K; Takada, G; Okamura-Ikeda, K; Motokawa, Y (30 April 1993). "Isolation and sequence determination of cDNA encoding human T-protein of the glycine cleavage system". Biochemical and Biophysical Research Communications. 192 (2): 766–71. doi:10.1006/bbrc.1993.1480. PMID 7916605.
  4. Okamura-Ikeda, K; Hosaka, H; Yoshimura, M; Yamashita, E; Toma, S; Nakagawa, A; Fujiwara, K; Motokawa, Y; Taniguchi, H (2 September 2005). "Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia". Journal of Molecular Biology. 351 (5): 1146–59. doi:10.1016/j.jmb.2005.06.056. PMID 16051266.
  5. Fujiwara, K; Okamura-Ikeda, K; Motokawa, Y (10 September 1984). "Mechanism of the glycine cleavage reaction. Further characterization of the intermediate attached to H-protein and of the reaction catalyzed by T-protein". The Journal of Biological Chemistry. 259 (17): 10664–8. PMID 6469978.
  6. Okamura-Ikeda, K; Fujiwara, K; Motokawa, Y (15 May 1987). "Mechanism of the glycine cleavage reaction. Properties of the reverse reaction catalyzed by T-protein". The Journal of Biological Chemistry. 262 (14): 6746–9. PMID 3571285.
  7. Aliefendioğlu, D; Tana Aslan, Ay; Coşkun, T; Dursun, A; Cakmak, FN; Kesimer, M (February 2003). "Transient nonketotic hyperglycinemia: two case reports and literature review". Pediatric Neurology. 28 (2): 151–5. doi:10.1016/s0887-8994(02)00501-5. PMID 12699870.
  8. Bröer, S; Bailey, CG; Kowalczuk, S; Ng, C; Vanslambrouck, JM; Rodgers, H; Auray-Blais, C; Cavanaugh, JA; Bröer, A; Rasko, JE (December 2008). "Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters". The Journal of Clinical Investigation. 118 (12): 3881–92. doi:10.1172/jci36625. PMC 2579706. PMID 19033659.
  9. Steiner, RD; Sweetser, DA; Rohrbaugh, JR; Dowton, SB; Toone, JR; Applegarth, DA (February 1996). "Nonketotic hyperglycinemia: atypical clinical and biochemical manifestations". The Journal of Pediatrics. 128 (2): 243–6. doi:10.1016/s0022-3476(96)70399-2. PMID 8636821.
  10. Kure, S; Shinka, T; Sakata, Y; Osamu, N; Takayanagi, M; Tada, K; Matsubara, Y; Narisawa, K (1998). "A one-base deletion (183delC) and a missense mutation (D276H) in the T-protein gene from a Japanese family with nonketotic hyperglycinemia". Journal of Human Genetics. 43 (2): 135–7. doi:10.1007/s100380050055. PMID 9621520.
  11. Kure, S; Mandel, H; Rolland, MO; Sakata, Y; Shinka, T; Drugan, A; Boneh, A; Tada, K; Matsubara, Y; Narisawa, K (April 1998). "A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia". Human Genetics. 102 (4): 430–4. doi:10.1007/s004390050716. PMID 9600239.
  12. Kure, S; Korman, SH; Kanno, J; Narisawa, A; Kubota, M; Takayanagi, T; Takayanagi, M; Saito, T; Matsui, A; Kamada, F; Aoki, Y; Ohura, T; Matsubara, Y (May 2006). "Rapid diagnosis of glycine encephalopathy by 13C-glycine breath test". Annals of Neurology. 59 (5): 862–7. doi:10.1002/ana.20853. PMID 16634033.
  13. Kure, S; Kato, K; Dinopoulos, A; Gail, C; DeGrauw, TJ; Christodoulou, J; Bzduch, V; Kalmanchey, R; Fekete, G; Trojovsky, A; Plecko, B; Breningstall, G; Tohyama, J; Aoki, Y; Matsubara, Y (April 2006). "Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia". Human Mutation. 27 (4): 343–52. doi:10.1002/humu.20293. PMID 16450403.
  14. Toone, JR; Applegarth, DA; Coulter-Mackie, MB; James, ER (April 2001). "Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): a strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH)". Molecular Genetics and Metabolism. 72 (4): 322–5. doi:10.1006/mgme.2001.3158. PMID 11286506.

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