title: A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants.
abstract: The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods. Phosphorylation seems to play an important role in the functioning of this flavoprotein. MTHFR catalyzes an irreversible reaction in homocysteine metabolism. Phosphorylation decreases the activity of MTHFR by enhancing the sensitivity of the enzyme to SAdenosylmethione. Two common polymorphisms in MTHFR, Ala222Val and Glu429Ala, can result in a number of vascular diseases. Effects of the Glu429Ala polymorphism on the structure of human MTHFR remain undetermined due to limited structural information. Hence, structural models of the MTHFR mutants were constructed using I-TASSER and assessed by PROCHECK, DFIRE and Verify3D tools. A mechanism is further suggested for the decreased activity of the Ala222Val and Glu429Ala mutants due to a decrease in number of serine phosphorylation sites using information gleaned from the molecular models. This provides insights for the understanding of structure-function relationship for MTHFR.
authors.affiliation: Illinois Informatics Institute, University of Illinois, Urbana-Champaign, Illinois, U.S.A ; Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Khuram
authors.initials: K
authors.lastname: Shahzad
authors.forename: Abdul
authors.initials: A
authors.lastname: Hai
authors.forename: Asifa
authors.initials: A
authors.lastname: Ahmed
authors.forename: Nadeem
authors.initials: N
authors.lastname: Kizilbash
authors.forename: Jamal
authors.initials: J
authors.lastname: Alruwaili
keywords: 5,10-Methylenetetrahydrofolate; Methylenetetrahydrofolate Reductase; Methylenetetrahydrofolate Reductase phosphorylation; hyperhomocysteinemia; in silico modeling