Aminomethyltransferase

Last updated
AMT
AMT-Aminomethiltransferase.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AMT , aminomethyltransferase, GCE, GCST, GCVT, NKH
External IDs OMIM: 238310 MGI: 3646700 HomoloGene: 409 GeneCards: AMT
Orthologs
SpeciesHumanMouse
Entrez

275

434437

Ensembl

ENSG00000145020

ENSMUSG00000032607

UniProt

P48728

Q8CFA2

RefSeq (mRNA)

NM_000481
NM_001164710
NM_001164711
NM_001164712

NM_001013814

RefSeq (protein)

NP_000472
NP_001158182
NP_001158183
NP_001158184

NP_001013836

Location (UCSC) Chr 3: 49.42 – 49.42 Mb Chr 9: 108.17 – 108.18 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Aminomethyltransferase
Identifiers
EC no. 2.1.2.10
CAS no. 37257-08-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
Aminomethyltransferase
AMT-Aminomethiltransferase.jpg
Crystallographic structure of human AMT. [5]
Identifiers
SymbolAMT
NCBI gene 275
HGNC AMT 473 AMT
OMIM 238310
PDB 1WSR
RefSeq NM_000481
UniProt P48728
Other data
EC number 2.1.2.10
Locus Chr. 3 p21.2-21.1
Search for
Structures Swiss-model
Domains InterPro

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

Contents

Structure

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. [6] 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. [7]

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. [8]

Function

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. [9] [10]

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. [11] 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. [12] [13] Enzymatic confirmation of the diagnosis relies on measurement of glycine cleavage system (GCS) enzyme activity in liver obtained by open biopsy or autopsy. [14] [15] 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. [16] [17] [18]

Related Research Articles

<span class="mw-page-title-main">Glycine encephalopathy</span> Medical condition

Glycine encephalopathy is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebrospinal fluid.

<span class="mw-page-title-main">Hyperekplexia</span> Genetic disorder causing an exaggerated startle response

Hyperekplexia is a very rare neurologic disorder, classically characterised by a pronounced startle responses to tactile or acoustic stimuli and an ensuing period of hypertonia. The hypertonia may be predominantly truncal, attenuated during sleep, or less prominent after one year of age.

<span class="mw-page-title-main">Serine dehydratase</span>

Serine dehydratase or L-serine ammonia lyase (SDH) is in the β-family of pyridoxal phosphate-dependent (PLP) enzymes. SDH is found widely in nature, but its structural and properties vary among species. SDH is found in yeast, bacteria, and the cytoplasm of mammalian hepatocytes. SDH catalyzes is the deamination of L-serine to yield pyruvate, with the release of ammonia.

<span class="mw-page-title-main">Citrin</span> Mammalian protein found in Homo sapiens

Citrin, also known as solute carrier family 25, member 13 (citrin) or SLC25A13, is a protein which in humans is encoded by the SLC25A13 gene.

<span class="mw-page-title-main">Glycine dehydrogenase (decarboxylating)</span> Protein-coding gene in the species Homo sapiens

Glycine decarboxylase also known as glycine cleavage system P protein or glycine dehydrogenase is an enzyme that in humans is encoded by the GLDC gene.

<span class="mw-page-title-main">G6PC</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase, catalytic subunit is an enzyme that in humans is encoded by the G6PC gene.

<span class="mw-page-title-main">Phosphate carrier protein, mitochondrial</span>

Phosphate carrier protein, mitochondrial is a protein that in humans is encoded by the SLC25A3 gene. The encoded protein is a transmembrane protein located in the mitochondrial inner membrane and catalyzes the transport of phosphate ions across it for the purpose of oxidative phosphorylation. There are two significant isoforms of this gene expressed in human cells, which differ slightly in structure and function. Mutations in this gene can cause mitochondrial phosphate carrier deficiency (MPCD), a fatal disorder of oxidative phosphorylation symptomized by lactic acidosis, neonatal hypotonia, hypertrophic cardiomyopathy, and death within the first year of life.

<span class="mw-page-title-main">Sodium- and chloride-dependent glycine transporter 2</span> Protein-coding gene in the species Homo sapiens

Sodium- and chloride-dependent glycine transporter 2, also known as glycine transporter 2 (GlyT2), is a protein that in humans is encoded by the SLC6A5 gene.

<span class="mw-page-title-main">NDUFV2</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial (NDUFV2) is an enzyme that in humans is encoded by the NDUFV2 gene. The encoded protein, NDUFV2, is a subunit of complex I of the mitochondrial respiratory chain, which is located on the inner mitochondrial membrane and involved in oxidative phosphorylation. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy.

<span class="mw-page-title-main">GCSH</span> Protein-coding gene in the species Homo sapiens

Glycine cleavage system H protein, mitochondrial is a protein that in humans is encoded by the GCSH gene. Degradation of glycine is brought about by the glycine cleavage system (GCS), which is composed of 4 protein components: P protein, H protein, T protein, and L protein. The H protein shuttles the methylamine group of glycine from the P protein to the T protein. The protein encoded by GCSH gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH). Two transcript variants, one protein-coding and the other probably not protein-coding, have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.

<span class="mw-page-title-main">NDUFS6</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial is an enzyme that in humans is encoded by the NDUFS6 gene.

<span class="mw-page-title-main">UQCRC2</span> Protein-coding gene in the species Homo sapiens

Cytochrome b-c1 complex subunit 2, mitochondrial (UQCRC2), also known as QCR2, UQCR2, or MC3DN5 is a protein that in humans is encoded by the UQCRC2 gene. The product of UQCRC2 is a subunit of the respiratory chain protein Ubiquinol Cytochrome c Reductase, which consists of the products of one mitochondrially encoded gene, MTCYTB and ten nuclear genes: UQCRC1, UQCRC2, Cytochrome c1, UQCRFS1, UQCRB, "11kDa protein", UQCRH, Rieske Protein presequence, "cyt. c1 associated protein", and "Rieske-associated protein." Defects in UQCRC2 are associated with mitochondrial complex III deficiency, nuclear, type 5.

<span class="mw-page-title-main">Glycine cleavage system</span>

The glycine cleavage system (GCS) is also known as the glycine decarboxylase complex or GDC. The system is a series of enzymes that are triggered in response to high concentrations of the amino acid glycine. The same set of enzymes is sometimes referred to as glycine synthase when it runs in the reverse direction to form glycine. The glycine cleavage system is composed of four proteins: the T-protein, P-protein, L-protein, and H-protein. They do not form a stable complex, so it is more appropriate to call it a "system" instead of a "complex". The H-protein is responsible for interacting with the three other proteins and acts as a shuttle for some of the intermediate products in glycine decarboxylation. In both animals and plants, the glycine cleavage system is loosely attached to the inner membrane of the mitochondria. Mutations in this enzymatic system are linked with glycine encephalopathy.

<span class="mw-page-title-main">ALDH7A1</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 7 family, member A1, also known as ALDH7A1 or antiquitin, is an enzyme that in humans is encoded by the ALDH7A1 gene. The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified.

<span class="mw-page-title-main">GLRX5</span> Protein-coding gene in the species Homo sapiens

Glutaredoxin 5, also known as GLRX5, is a protein which in humans is encoded by the GLRX5 gene located on chromosome 14. This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iron- sulfur clusters, which are required for normal iron homeostasis. Mutations in this gene are associated with autosomal recessive pyridoxine-refractory sideroblastic anemia.

Lipoate–protein ligase (EC 2.7.7.63, LplA, lipoate protein ligase, lipoate–protein ligase A, LPL, LPL-B) is an enzyme with systematic name ATP:lipoate adenylyltransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">SLC25A22</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 25 member 22 is a protein that in humans is encoded by the SLC25A22 gene. This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Expression of this gene is increased in colorectal tumor cells.

<span class="mw-page-title-main">LIAS (gene)</span> Protein-coding gene in the species Homo sapiens

Lipoic acid synthetase is a protein that in humans is encoded by the LIAS gene.

<span class="mw-page-title-main">NDUFAF2</span> Protein-coding gene in the species Homo sapiens

NADH:ubiquinone oxidoreductase complex assembly factor 2 (NDUFAF2), also known as B17.2L or NDUFA12L is a protein that in humans is encoded by the NDUFAF2, or B17.2L, gene. The NDUFAF2 protein is a chaperone involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with progressive encephalopathy and Leigh disease resulting from mitochondrial complex I deficiency.

NADH:ubiquinone oxidoreductase complex assembly factor 5, also known as Arginine-hydroxylase NDUFAF5, or Putative methyltransferase NDUFAF5, is a protein that in humans is encoded by the NDUFAF5 gene. The NADH-ubiquinone oxidoreductase complex of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145020 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032607 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. doi: 10.1016/S0021-9258(18)90562-4 . PMID   6469978.
  10. ↑ 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. doi: 10.1016/S0021-9258(18)48307-X . PMID   3571285.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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. S2CID   20224399.
  16. ↑ 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. S2CID   34980421.
  17. ↑ 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. S2CID   26911122.
  18. ↑ 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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