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Mechanistic basis of uphill electron transfer and reductive methylation in the human MS¿MSR electron transfer complex

Reference	BB/C00390X/1
Principal Investigator / Supervisor	Professor Nigel Scrutton
Co-Investigators / Co-Supervisors	Professor David Leys, Professor Andrew Munro, Dr Stephen Rigby, Dr Kirsten Wolthers
Institution	University of Leicester
Department	Biochemistry
Funding type	Research
Value (£)	237,482
Status	Completed
Type	Research Grant
Start date	01/02/2005
End date	31/08/2005
Duration	7 months

Abstract

Methionine synthase reductase (MSR) is a key eukaryotic enzyme of folate and cobalamin metabolism, involved in the reductive activation of methionine synthase (MS). MS is required for the folate/cobalamin-dependent conversion of homocysteine to methionine and cycles between the highly reactive cobalamin (I) cofactor and the cobalamin (III) species. Over time (every 100 to 2000 cycles) the cobalamin (I) cofactor is oxidised to the inert cobalamin (II) form, rendering MS inactive. MS must then be reactivated through reductive methylation using S-adenosylmethionine as the methyl donor, involving MSR. A similar reductive reactivation is required for bacterial MS, but in this case flavodoxin, which is not found in eukaryotic organisms, is the electron donor. This proposal addresses the mechanism of electron transfer from MSR to MS, and the conformational changes that modulate cobalamin-dependent chemistry in the active site of MS on forming the MS-MSR complex. In particular, the need to transfer electrons endergonically and to couple MSR binding to changes in active site chemistry in MS are addressed. The work will lead to a detailed mechanistic and structural understanding of reductive methylation in the MS-MSR complex from which the consequences of clinically relevant mutations and polymorphic variations can be rationalised from the mechanistic viewpoint. The work involves detailed fast reaction kinetic, spectroscopic and potentiometric analysis of the MS-MSR complex to provide a detailed understanding of enzyme turnover in this complex mammalian enzyme.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/C00390X/2 Mechanistic basis of uphill electron transfer and reductive methylation in the human MSMSR electron transfer complex

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