Journal
AMINO ACIDS
Volume 53, Issue 12, Pages 1817-1834Publisher
SPRINGER WIEN
DOI: 10.1007/s00726-021-02999-5
Keywords
Proline metabolism; Pyrroline-5-carboxylate reductase; PYCR; Proline biosynthesis; Cancer
Categories
Funding
- NIGMS, National Institutes of Health [R01GM132640]
- Wayne L. Ryan Fellowship through The Ryan Foundation
Ask authors/readers for more resources
Proline metabolism plays a significant role in cancer cells, involving upregulation of proline biosynthetic genes and the dual function of proline catabolic enzyme in promoting cancer and apoptosis. The cycling of proline impacts cellular growth and death pathways. PYCR, the last enzyme in proline biosynthesis, is crucial for the proline metabolic cycle and has been shown to be widely upregulated in various cancer types.
Proline metabolism features prominently in the unique metabolism of cancer cells. Proline biosynthetic genes are consistently upregulated in multiple cancers, while the proline catabolic enzyme proline dehydrogenase has dual, context-dependent pro-cancer and pro-apoptotic functions. Furthermore, the cycling of proline and Delta(1)-pyrroline-5-carboxylate through the proline cycle impacts cellular growth and death pathways by maintaining redox homeostasis between the cytosol and mitochondria. Here we focus on the last enzyme of proline biosynthesis, Delta(1)-pyrroline-5-carboxylate reductase, known as PYCR in humans. PYCR catalyzes the NAD(P)H-dependent reduction of Delta(1)-pyrroline-5-carboxylate to proline and forms the reductive half of the proline metabolic cycle. We review the research on the three-dimensional structure, biochemistry, inhibition, and cancer biology of PYCR. To provide a global view of PYCR gene upregulation in cancer, we mined RNA transcript databases to analyze differential gene expression in 28 cancer types. This analysis revealed strong, widespread upregulation of PYCR genes, especially PYCR1. Altogether, the research over the past 20 years makes a compelling case for PYCR as a cancer therapy target. We conclude with a discussion of some of the major challenges for the field, including developing isoform-specific inhibitors, elucidating the function of the long C-terminus of PYCR1/2, and characterizing the interactome of PYCR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available