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Functional Impact of a Cancer-Related Variant in Human Δ^1^-Pyrroline-5-Carboxylate Reductase 1 by Oseeyi I. Daudu; Kaylen R. Meeks; Lu Zhang; Javier Seravalli; John J. Tanner; Donald F. Becker is a Engineering article available to read on EtoBox.

What is Functional Impact of a Cancer-Related Variant in Human Δ^1^-Pyrroline-5-Carboxylate Reductase 1 about?

Pyrroline-5-carboxylate reductase (PYCR) is a proline biosynthetic enzyme that catalyzes the NAD(P)H-dependent reduction of Δ^1^-pyrroline-5-carboxylate (P5C) to proline. Humans have three PYCR isoforms, with PYCR1 often upregulated in different types of cancers. Here, we studied the biochemical and structural properties of the Thr171Met variant of PYCR1, which is found in patients with malignant melanoma and lung adenocarcinoma. Although PYCR1 is strongly associated with cancer progression, characterization of a PYCR1 variant in cancer patients has not yet been reported. Thr171 is conserved in all three PYCR isozymes and is located near the P5C substrate binding site. We found that the amino acid replacement does not affect thermostability but has a profound effect on PYCR1 catalytic activity. The __k__~cat~ of the PYCR1 variant T171M is 100- to 200-fold lower than wild-type PYCR1 when P5C is the variable substrate, and 10- to 25-fold lower when NAD(P)H is varied. A 1.84 Å resolution X-ray crystal structure of T171M reveals that the Met side chain invades the P5C substrate binding site, suggesting that the catalytic defect is due to steric clash preventing P5C from achieving the o

Who reads Functional Impact of a Cancer-Related Variant in Human Δ^1^-Pyrroline-5-Carboxylate Reductase 1?

Author

Oseeyi I. Daudu; Kaylen R. Meeks; Lu Zhang; Javier Seravalli; John J. Tanner; Donald F. Becker

Publisher

American Chemical Society (ACS)

Published

2023

Language

EN

Field

Engineering (Physical Sciences)