Biochemistry. 2018 Jun 26;57(25):3433-3444. doi: 10.1021/acs.biochem.8b00215. Epub 2018 Apr 23.
The Proline Cycle As a Potential Cancer Therapy Target.
Abstract
Interest
in how proline contributes to cancer biology is expanding because of
the emerging role of a novel proline metabolic cycle in cancer cell
survival, proliferation, and metastasis. Proline biosynthesis and
degradation involve the shared intermediate Δ1-pyrroline-5-carboxylate
(P5C), which forms l-glutamate-γ-semialdehyde (GSAL) in a reversible
non-enzymatic reaction. Proline is synthesized from glutamate or ornithine
through GSAL/P5C, which is reduced to proline by P5C reductase (PYCR)
in a NAD(P)H-dependent reaction. The degradation of proline occurs in
the mitochondrion and involves two oxidative steps catalyzed by proline
dehydrogenase (PRODH) and GSAL dehydrogenase (GSALDH). PRODH is a
flavin-dependent enzyme that couples proline oxidation with reduction of
membrane-bound quinone, while GSALDH catalyzes the NAD+-dependent
oxidation of GSAL to glutamate. PRODH and PYCR form a metabolic
relationship known as the proline-P5C cycle, a novel pathway that
impacts cellular growth and death pathways. The proline-P5C cycle has
been implicated in supporting ATP production, protein and nucleotide
synthesis, anaplerosis, and redox homeostasis in cancer cells. This
Perspective details the structures and reaction mechanisms of PRODH and
PYCR and the role of the proline-P5C cycle in cancer metabolism. A major
challenge in the field is to discover inhibitors that specifically
target PRODH and PYCR isoforms for use as tools for studying proline
metabolism and the functions of the proline-P5C cycle in cancer. These
molecular probes could also serve as lead compounds in cancer drug
discovery targeting the proline-P5C cycle.
- PMID:
- 29648801
- PMCID:
- PMC6026536
- [Available on 2019-06-26]
- DOI:
- 10.1021/acs.biochem.8b00215
- [Indexed for MEDLINE]
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