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|2o2k, resolution 1.60Å ()|
|Gene:||MTR (Homo sapiens)|
Crystal Structure of the Activation Domain of Human Methionine Synthase Isoform/Mutant D963E/K1071N
Human methionine synthase (hMS) is a multidomain cobalamin-dependent enzyme that catalyses the conversion of homocysteine to methionine by methyl group transfer. We report here the 1.6 A crystal structure of the C-terminal activation domain of hMS. The structure is C-shaped with the core comprising mixed alpha and beta regions, dominated by a twisted antiparallel beta sheet with a beta-meander region. These features, including the positions of the active-site residues, are similar to the activation domain of Escherichia coli cobalamin-dependent MS (MetH). Structural and solution studies suggest a small proportion of hMS activation domain exists in a dimeric form, which contrasts with the monomeric form of the E. coli homologue. Fluorescence studies show that human activation domain interacts with the FMN-binding domain of human methionine synthase reductase (hMSR). This interaction is enhanced in the presence of S-adenosyl-methionine. Binding of the D963E/K1071N mutant activation domain to the FMN domain of MSR is weaker than with wild-type activation domain. This suggests that one or both of the residues D963 and K1071 are important in partner binding. Key differences in the sequences and structures of hMS and MetH activation domains are recognized and include a major reorientation of an extended 3(10)-containing loop in the human protein. This structural alteration might reflect differences in their respective reactivation complexes and/or potential for dimer formation. The reported structure is a component of the multidomain hMS : MSR complex, and represents an important step in understanding the impact of clinical mutations and polymorphisms in this key electron transfer complex.
Crystal structure and solution characterization of the activation domain of human methionine synthase., Wolthers KR, Toogood HS, Jowitt TA, Marshall KR, Leys D, Scrutton NS, FEBS J. 2007 Feb;274(3):738-50. PMID:17288554
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[METH_HUMAN] Defects in MTR are the cause of methylcobalamin deficiency type G (cblG) [MIM:250940]; also known as homocystinuria-megaloblastic anemia complementation type G. It is an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria. Mild deficiency in MS activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects. MS mutations could also be involved in tumorigenesis. Defects in MTR may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM:601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Genetic defects in MTR may affect the risk of spina bifida via the maternal rather than the embryonic genotype.
[METH_HUMAN] Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity).
About this Structure
- Wolthers KR, Toogood HS, Jowitt TA, Marshall KR, Leys D, Scrutton NS. Crystal structure and solution characterization of the activation domain of human methionine synthase. FEBS J. 2007 Feb;274(3):738-50. PMID:17288554 doi:10.1111/j.1742-4658.2006.05618.x
- ↑ Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, Mitchell LE. Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet. 2002 Nov;71(5):1222-6. Epub 2002 Oct 9. PMID:12375236 doi:S0002-9297(07)60417-0
- ↑ O'Leary VB, Mills JL, Pangilinan F, Kirke PN, Cox C, Conley M, Weiler A, Peng K, Shane B, Scott JM, Parle-McDermott A, Molloy AM, Brody LC. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab. 2005 Jul;85(3):220-7. Epub 2005 Mar 17. PMID:15979034 doi:S1096-7192(05)00052-1