Human Δ1-pyrroline-5-carboxylate synthase: Function and regulation

C. A.A. Hu, S. Khalil, S. Zhaorigetu, Z. Liu, M. Tyler, G. Wan, D. Valle

Research output: Contribution to journalArticlepeer-review

Abstract

Mammalian Δ1-pyrroline-5-carboxylate synthase (P5CS) is a bifunctional ATP- and NAD(P)H-dependent mitochondrial enzyme that catalyzes the coupled phosphorylation and reduction-conversion of l-glutamate to P5C, a pivotal step in the biosynthesis of l-proline, l-ornithine and l-arginine. Previously, we reported cloning and characterization of two P5CS transcript variants generated by exon sliding that encode two protein isoforms differing only by a two amino acid-insert at the N-terminus of the γ-glutamyl kinase active site. The short form (P5CS.short) is highly expressed in the gut and is inhibited by ornithine. In contrast, the long form (P5CS.long) is expressed ubiquitously and is insensitive to ornithine. Interestingly, we found that all the established human cell lines we have studied expressed P5CS.long but not P5CS.short. In addition, expression of P5CS.long can be modulated by hormones: downregulation by hydrocortisone and dexamethasone and upregulation by estradiol, for example. Using a quantitative proteomic approach, we showed that P5CS.long is upregulated by p53 in p53-induced apoptosis in DLD-1 colorectal cancer cells. Functional genomic analysis confirmed that there are two p53-binding consensus sequences in the promoter region and in the intron 1 of the human P5CS gene. Interestingly, overexpression of P5CS by adenoviruses harboring P5CS.long or P5CS.short in various cell types has no effect on cell growth or survival. It would be of importance to further investigate the role of P5CS as a p53 downstream effector and how P5CS.short expression is regulated by hormones and factors of alternative splicing in cells isolated from model animals.

Original languageEnglish (US)
Pages (from-to)665-672
Number of pages8
JournalAmino Acids
Volume35
Issue number4
DOIs
StatePublished - Nov 2008

Keywords

  • Alternative splicing
  • Apoptosis
  • Exon sliding
  • Hormones
  • L-Proline
  • P53
  • P5C synthase (P5CS)
  • Prostate cancer (PCa) cells
  • Quantitative proteomics
  • Δ-Pyrroline-5-carboxylate (P5C)

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

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