Regulation of carbamoylphosphate synthesis in Escherichia coli: an amazing metabolite at the crossroad of arginine and pyrimidine biosynthesis

Daniel Charlier, Phu Nguyen Le Minh, Martine Roovers

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In all organisms carbamoylphosphate (CP) is a precursor common to the synthesis of arginine and pyrimidines. In Escherichia coli and most other Gram-negative bacteria, CP is produced by a single enzyme, carbamoylphosphate synthase (CPSase), encoded by the carAB operon. This particular situation poses a question of basic physiological interest: what are the metabolic controls coordinating the synthesis and distribution of this high-energy substance in view of the needs of both pathways? The study of the mechanisms has revealed unexpected moonlighting gene regulatory activities of enzymes and functional links between mechanisms as diverse as gene regulation and site-specific DNA recombination. At the level of enzyme production, various regulatory mechanisms were found to cooperate in a particularly intricate transcriptional control of a pair of tandem promoters. Transcription initiation is modulated by an interplay of several allosteric DNA binding transcription factors using effector molecules from three different pathways (arginine, pyrimidines, purines), nucleoid associated factors (NAPs), trigger enzymes (enzymes with a second unlinked gene regulatory function), DNA remodeling (bending and wrapping), UTP-dependent reiterative transcription initiation, and stringent control by the alarmone ppGpp. At the enzyme level, CPSase activity is tightly controlled by allosteric effectors originating from different pathways: an inhibitor (UMP) and two activators (ornithine and IMP) that antagonize the inhibitory effect of UMP. Furthermore, it is worth noticing that all reaction intermediates in the production of CP are extremely reactive and unstable, and protected by tunneling through a 96 Å long internal channel.
Original languageEnglish
Pages (from-to)1647–1661
Number of pages15
JournalAmino Acids
Volume50
Issue number12
DOIs
Publication statusPublished - 20 Sep 2018

Keywords

  • Allosteric control
  • Arginine biosynthesis
  • Carbamoylphosphate synthase
  • DNA remodeling
  • Tandem promoters
  • Transcription regulation

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