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The three-dimensional structural basis of type II hyperprolinemia.

Dhiraj Srivastava1, Ranjan K Singh, Michael A Moxley

  • 1Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA.

Journal of Molecular Biology
|April 21, 2012
PubMed
Summary
This summary is machine-generated.

Type II hyperprolinemia is caused by a deficient enzyme, P5CDH. A mutation at Ser352 to Leu inactivates P5CDH by disrupting its structure and NAD+ binding, explaining the disorder.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Type II hyperprolinemia results from a deficiency in Δ(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH), an enzyme crucial for glutamate synthesis.
  • P5CDH (ALDH4A1) catalyzes the oxidation of glutamate semialdehyde to glutamate.

Purpose of the Study:

  • To determine the first crystal structure of human P5CDH (HsP5CDH).
  • To investigate the structural and catalytic impact of the hyperprolinemia-associated Ser352 to Leu mutation on HsP5CDH.

Main Methods:

  • X-ray crystallography was used to determine the structures of HsP5CDH, S352A, and S352L mutants.
  • High-resolution structures of mouse P5CDH were obtained complexed with sulfate, glutamate, and NAD+.

Main Results:

  • The Ser352 to Leu mutation abolishes catalytic activity and NAD+ binding.
  • Structural analysis revealed that the mutation causes a significant rearrangement of the catalytic loop, affecting substrate and cofactor binding.
  • The S352A mutant data indicate the nonpolar Leu side chain, not the loss of the hydroxyl group, is responsible for the functional defects.

Conclusions:

  • The Ser352 to Leu mutation in P5CDH leads to enzyme inactivation through significant structural rearrangements.
  • These findings provide a molecular basis for Type II hyperprolinemia and highlight the critical role of Ser352 in P5CDH function.