| Structural highlights
1wsr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Related: | 1wsv |
| Gene: | GCST (Homo sapiens) |
| Activity: | Aminomethyltransferase, with EC number 2.1.2.10 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[GCST_HUMAN] Defects in AMT are a cause of non-ketotic hyperglycinemia (NKH) [MIM:605899]; also known as glycine encephalopathy (GCE). NKH is an autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms.[1] [2] [3] [4] [5]
Function
[GCST_HUMAN] The glycine cleavage system catalyzes the degradation of glycine.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
T-protein, a component of the glycine cleavage system, catalyzes the formation of ammonia and 5,10-methylenetetrahydrofolate from the aminomethyl moiety of glycine attached to the lipoate cofactor of H-protein. Several mutations in the human T-protein gene cause non-ketotic hyperglycinemia. To gain insights into the effect of disease-causing mutations and the catalytic mechanism at the molecular level, crystal structures of human T-protein in free form and that bound to 5-methyltetrahydrofolate (5-CH3-H4folate) have been determined at 2.0 A and 2.6 A resolution, respectively. The overall structure consists of three domains arranged in a cloverleaf-like structure with the central cavity, where 5-CH3-H4folate is bound in a kinked shape with the pteridine group deeply buried into the hydrophobic pocket and the glutamyl group pointed to the C-terminal side surface. Most of the disease-related residues cluster around the cavity, forming extensive hydrogen bonding networks. These hydrogen bonding networks are employed in holding not only the folate-binding space but also the positions and the orientations of alpha-helix G and the following loop in the middle region, which seems to play a pivotal role in the T-protein catalysis. Structural and mutational analyses demonstrated that Arg292 interacts through water molecules with the folate polyglutamate tail, and that the invariant Asp101, located close to the N10 group of 5-CH3-H4folate, might play a key role in the initiation of the catalysis by increasing the nucleophilic character of the N10 atom of the folate substrate for the nucleophilic attack on the aminomethyl lipoate intermediate. A clever mechanism of recruiting the aminomethyl lipoate arm to the reaction site seems to function as a way of avoiding the release of toxic formaldehyde.
Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia.,Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H J Mol Biol. 2005 Sep 2;351(5):1146-59. PMID:16051266[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nanao K, Okamura-Ikeda K, Motokawa Y, Danks DM, Baumgartner ER, Takada G, Hayasaka K. Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia. Hum Genet. 1994 Jun;93(6):655-8. PMID:8005589
- ↑ Kure S, Mandel H, Rolland MO, Sakata Y, Shinka T, Drugan A, Boneh A, Tada K, Matsubara Y, Narisawa K. A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia. Hum Genet. 1998 Apr;102(4):430-4. PMID:9600239
- ↑ Kure S, Shinka T, Sakata Y, Osamu N, Takayanagi M, Tada K, Matsubara Y, Narisawa K. A one-base deletion (183delC) and a missense mutation (D276H) in the T-protein gene from a Japanese family with nonketotic hyperglycinemia. J Hum Genet. 1998;43(2):135-7. PMID:9621520 doi:10.1007/s100380050055
- ↑ Toone JR, Applegarth DA, Coulter-Mackie MB, James ER. Biochemical and molecular investigations of patients with nonketotic hyperglycinemia. Mol Genet Metab. 2000 Jun;70(2):116-21. PMID:10873393 doi:10.1006/mgme.2000.3000
- ↑ Toone JR, Applegarth DA, Coulter-Mackie MB, James ER. 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). Mol Genet Metab. 2001 Apr;72(4):322-5. PMID:11286506 doi:10.1006/mgme.2001.3158
- ↑ Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H. Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia. J Mol Biol. 2005 Sep 2;351(5):1146-59. PMID:16051266 doi:http://dx.doi.org/10.1016/j.jmb.2005.06.056
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