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Title

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

 

Authors

Khuram Shahzad1,2, Abdul Hai3, Asifa Ahmed2, Nadeem Kizilbash3* & Jamal Alruwaili3

 

Affiliation

1Illinois Informatics Institute, University of Illinois, Urbana-Champaign, Illinois, U.S.A; 2Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan; 3Department of Biochemistry, Faculty of Medicine & Applied Medical Sciences, Northern Border University, Arar-91431, Saudi Arabia

 

Email

fsd707@gmail.com; *Corresponding author

 

Article Type

Hypothesis

 

Date

Received September 23, 2013; Accepted September 30, 2013; Published November 11, 2013

 

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 S-Adenosylmethione. 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.

 

Keywords

Methylenetetrahydrofolate Reductase, in silico modeling, hyperhomocysteinemia, 5,10-Methylenetetrahydrofolate, Methylenetetrahydrofolate Reductase phosphorylation.

 

Citation

Shahzad et al.  Bioinformation 9(18): 929-936 (2013)

 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.