A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants.

Khuram Shahzad,Nadeem Kizilbash,Jamal Alruwaili,Abdul Hai,Asifa Ahmed

doi:10.6026/97320630009929

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.

Highlights

The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods
NADH-dependent MTHFR from E. coli is insensitive to S-Adenosylmethionine [5]
Two experimentally determined structures were present in the Protein Data Bank (PDB), namely from E. coli (PDB code: 1b5t) [38] and from Thermus thermophilus (PDB code:1v93) [39, 40]

Summary

Introduction

The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods. 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. Methylenetetrahydrofolate reductase (MTHFR) plays an of the native enzyme with trypsin It contains a bound FAD important role in processing of amino acids. BIOINFORMATION open access of about 37 kDa. The C-terminus of human MTHFR contains the S-Adenosylmethionine-binding site which regulates the Methionine level in cells [4]. NADH-dependent MTHFR from E. coli is insensitive to S-Adenosylmethionine [5]

Methods

Discussion

Conclusion