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.
Highlights
Carbamyl phosphate (CP), discovered and synthesized by Jones and Lipmann in 1955 [1], is an interesting compound combining ammonia, carbonate, and phosphate in a single molecule
carbamyl phosphate synthetase (CPS) have arisen by gene duplication, translocation, and fusion of an ancestral ATP grasp fold kinase followed by the independent mutation of the domains for more specialized functions and the acquisition of a glutaminase able to use glutamine as a nitrogen-donating substrate [43,44,45,46]
Since CK-like CPS plays an anabolic role in vivo to produce CP needed for the synthesis of pyrimidine and arginine, we will term this CP-like CPS as anabolic CK, in order to distinguish it from closely related carbamate kinases, which use CP generated from catabolic transcarbamylases to make ATP [10]
Summary
Carbamyl phosphate (CP), discovered and synthesized by Jones and Lipmann in 1955 [1], is an interesting compound combining ammonia, carbonate, and phosphate in a single molecule. Which is broadly distributed from microorganisms to humans, uses a basic ATP-grasp fold enzyme [5]. Theitsecond one, claimed to exist only fold in microorganisms or as internally by the glutaminase domain; can be either fused to the ATP-grasp enzyme or associated with it as a subunit of aPyrococcus heterodimer. Can donate a phosphate to cartoon diagrams with the coordinates from Protein Data Bank (CPS, PDB ID: 5dou; aCK, PDB ID: ADP generating ATP using catabolic carbamate kinase (cCK). CP even participates in the [NiFe] hydrogenase maturation by providing the CN group to the [NiFe] cluster In this process, the hydrogenase pleiotropically acting protein A (HypA) catalyzes a carbamyl transfer reaction from carbamate, which is generated from CP, to the C-terminal cysteine residue of HypE via a carbamyladenylate intermediate [24]. It is an opportune time to summarize many facets of this important small molecule, which is a well-known essential intermediate of pyrimidine and arginine/urea biosynthesis and is highly correlated with human health
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