Activation of methyltetrahydrofolate by cobalamin-independent methionine synthase.

Biochemistry
Rebecca E Taurog, R G Matthews

Abstract

Cobalamin-independent methionine synthase (MetE) catalyzes the final step of de novo methionine synthesis using the triglutamate derivative of methyltetrahydrofolate (CH(3)-H(4)PteGlu(3)) as methyl donor and homocysteine (Hcy) as methyl acceptor. This reaction is challenging because at physiological pH the Hcy thiol is not a strong nucleophile and CH(3)-H(4)PteGlu(3) provides a very poor leaving group. Our laboratory has previously established that Hcy is ligated to a tightly bound zinc ion in the MetE active site. This interaction activates Hcy by lowering its pK(a), such that the thiolate is stabilized at neutral pH. The remaining chemical challenge is the activation of CH(3)-H(4)PteGlu(3). Protonation of N5 of CH(3)-H(4)PteGlu(3) would produce a better leaving group, but occurs with a pK(a) of 5 in solution. We have taken advantage of the sensitivity of the CH(3)-H(4)PteGlu(3) absorption spectrum to probe its protonation state when bound to MetE. Comparison of free and MetE-bound CH(3)-H(4)PteGlu(3) absorbance spectra indicated that the N5 is not protonated in the binary complex. Rapid reaction studies have revealed changes in CH(3)-H(4)PteGlu(3) absorbance that are consistent with protonation at N5. These absorbance changes...Continue Reading

References

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Citations

Dec 30, 2014·Journal of Molecular Biology·Devinder K Ubhi, Jon D Robertus
Jun 22, 2011·Archives of Biochemistry and Biophysics·Devinder UbhiJon D Robertus
Jul 19, 2012·Angewandte Chemie·Luka S KovacevicJohn A Murphy
Feb 4, 2021·PLoS Genetics·Morgan N PriceAdam P Arkin
Sep 1, 2008·EcoSal Plus·Jorge C Escalante-Semerena, Martin J Warren

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