Feb 17, 1981

pH properties and chemical mechanism of action of 3-hydroxy-3-methylglutaryl coenzyme A reductase

Biochemistry
D VelosoJ W Porter

Abstract

The pH variation of the kinetic parameters V and V/K for the oxidation of mevaldate by NADP+ in the presence of CoA (reverse reaction) and for the reduction of mevaldate by NADPH in the presence or absence of CoA (forward reaction) for the reactions catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was examined. In the reverse reaction a group, X, on the enzyme with a pK of 7.9 must be unprotonated for NADP+ binding and catalysis. The presence of NADP+ shifts this pK to a value below 6. The V/K profile for mevaldate shows that deprotonation of a group, Y, with a pK of 6.7 decreased the reaction rate by a factor of 27. In the forward reaction, the pK of the X group was about 6.9 except when CoA and mevaldate were both present, in which case it was shifted to 7.8. CoA decreased the Kms for mevaldate about 10-fold without changing the Vmax at the optimum protonation state. The catalytic group, X, was identified as a cationic acid, probably histidine. A catalytic mechanism is proposed in which the protonated form of histidine induces hydride transfer from the A side of NADPH by donating a proton to the carbonyl of HMG-CoA or to the aldehyde form of mevaldate. The role of the Y group, which from its pK of 6.7 an...Continue Reading

  • References18
  • Citations14

References

  • References18
  • Citations14

Citations

Mentioned in this Paper

In Vivo NMR Spectroscopy
Hydroxymethylglutaryl-CoA reductase
Dimethylformamide
Ampholytes
NADP
Mevaldic acid, (+-)-isomer
PRKACA
HMGCR
Sekumatic
Hydrogen-Ion Concentration

About this Paper

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