Sources and Fates of Carbamyl Phosphate: A Labile Energy-Rich Molecule with Multiple Facets

Abstract

Carbamyl phosphate (CP) is well-known as an essential intermediate of pyrimidine and arginine/urea biosynthesis. Chemically, CP can be easily synthesized from dihydrogen phosphate and cyanate. Enzymatically, CP can be synthesized using three different classes of enzymes: (1) ATP-grasp fold protein based carbamyl phosphate synthetase (CPS); (2) Amino-acid kinase fold carbamate kinase (CK)-like CPS (anabolic CK or aCK); and (3) Catabolic transcarbamylase. The first class of CPS can be further divided into three different types of CPS as CPS I, CPS II, and CPS III depending on the usage of ammonium or glutamine as its nitrogen source, and whether N-acetyl-glutamate is its essential co-factor. CP can donate its carbamyl group to the amino nitrogen of many important molecules including the most well-known ornithine and aspartate in the arginine/urea and pyrimidine biosynthetic pathways. CP can also donate its carbamyl group to the hydroxyl oxygen of a variety of molecules, particularly in many antibiotic biosynthetic pathways. Transfer of the carbamyl group to the nitrogen group is catalyzed by the anabolic transcarbamylase using a direct attack mechanism, while transfer of the carbamyl group to the oxygen group is catalyzed by a different class of enzymes, CmcH/NodU CTase, using a different mechanism involving a three-step reaction, decomposition of CP to carbamate and phosphate, transfer of the carbamyl group from carbamate to ATP to form carbamyladenylate and pyrophosphate, and transfer of the carbamyl group from carbamyladenylate to the oxygen group of the substrate. CP is also involved in transferring its phosphate group to ADP to generate ATP in the fermentation of many microorganisms. The reaction is catalyzed by carbamate kinase, which may be termed as catabolic CK (cCK) in order to distinguish it from CP generating CK. CP is a thermally labile molecule, easily decomposed into phosphate and cyanate, or phosphate and carbamate depending on the pH of the solution, or the presence of enzyme. Biological systems have developed several mechanisms including channeling between enzymes, increased affinity of CP to enzymes, and keeping CP in a specific conformation to protect CP from decomposition. CP is highly important for our health as both a lack of, or decreased, CP production and CP accumulation results in many disease conditions.

The carB Gene of Escherichia coli BL21(DE3) is Associated with Nematicidal Activity against the Root-Knot Nematode Meloidogyne javanica

“…The Tn5 transposon of MB12 was located within the carB gene, which encodes a large subunit of CPS. Carbamoyl phosphate is a vital small molecule that powers cell metabolism and can donate a carbamyl group within numerous well-known biosynthetic pathways, including the arginine/urea, pyrimidine and antibiotic synthesis pathways [ 40 , 41 ]. Besides being involved in biosynthetic pathways, carB has been recently reported to possess novel functions: disruption of carB in Xanthomonas citri subsp.…”

CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis

“…Figure 17.1 depicts this process as an assembly line, where the product of one enzyme acts as the substrate of the next, and the semi-finished intermediates move somehow between active centers. The metabolic pipeline starts with the manufacturing of carbamoyl phosphate (CP), a labile and high-energy phosphate metabolite that is also a common precursor for the de novo biosynthesis of arginine and urea (Jones 1980;Shi et al 2018). CP is made from bicarbonate, ammonia (obtained from glutamine hydrolysis) and two molecules of ATP, in a four-step reaction catalyzed by carbamoyl phosphate synthetase (CPS; EC 6.3.5.5), an enzyme actually composed of two activities, a glutamine-dependent amidotransferase (GLN) and a synthetase (SYN) (Meister 1989;Simmer et al 1990).…”

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

“…In hyperthermophilic archaea such as Pyrococcus species, a carbamate kinase rather than a CPSase appears to be responsible for CP synthesis (Purcarea et al 1996; Durbecq et al 1997; Rámon-Maiques et al 2000; Uriarte et al 1999; Marina et al 1999; Alcántara et al 2000). For additional information on CP producing and consuming enzymes in various organisms, including humans, the reader is referred to a recent review by Shi et al (2018).

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“…3) (Jones and Lipman 1960; Anderson and Meister 1965; Shi et al 2018). The preferred and physiologically relevant nitrogen donor for E. coli CPSase, and by extension for all bacterial CPSases, is glutamine (Piérard and Wiame 1964; Cunin et al 1986; Meister 1989) (Fig.…”