Document Type

Article

Publication Date

Summer 8-25-2016

Publication Title

Canadian Journal of Chemistry

Volume

94

First Page

1151

Last Page

1162

DOI

10.1139/cjc-2016-0286

Keywords

Computational chemistry, enzyme, molecular dynamics, substrate binding, inhibition, mutation

Abstract

The NAD+-dependent enzyme, 1-pyrroline-5-carboxylate dehydrogenase (P5CDH), has an important role in proline and hydroxyproline catabolism for humans. Specifically, this aldehyde dehydrogenase is responsible for the oxidation of both L-glutamate- -semialdehyde (GSA) and 4-erythro-hydroxy-L-glutamate- -semialdehyde (4-OH-GSA) to their respective L-glutamate product forms. We have performed a detailed molecular dynamics (MD) study of both the reactant and product complex structures of P5CDH to gain insights into ligand binding (i.e., GSA, 4-OH-GSA, NAD+, GLU) in the active site. Moreover, our investigations were further extended to examine the structural impact of S352L, S352A, and E314A mutations on the deficiency in the P5CDH enzymatic activity. Our in silico mutation analysis indicated that the conserved Glu447 has significantly shifted in both the S352L and E314A mutants, causing NAD+ to be displaced from its predictive orientation in the binding site and hence forming a catalytically inactive enzyme. However in the case of S352A, the catalytic site including the oxyanion hole and Cys348 remain virtually unchanged, and the coenzyme maintains its binding position.

Comments

First published in the Canadian Journal of Chemistry from NRC Research Press: dx.doi.org/10.1139/cjc-2016-0286

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