Guanosine monophosphate synthetase (GMPS) (GMPS)

Guanosine monophosphate synthetase (GMPS) is an essential enzyme in the de novo purine biosynthetic pathway, responsible for the final step in the synthesis of guanosine monophosphate (GMP) (UniProt P49915). It catalyzes the ATP-dependent amination of xanthosine 5'-monophosphate (XMP) to GMP, utilizing glutamine as a nitrogen donor (nih.gov, 1.1.1). Beyond its primary metabolic function, GMPS exhibits moonlighting activity by interacting with ubiquitin-specific protease 7 (USP7) to regulate histone deubiquitylation and gene expression (nih.gov, 1.1.5). Due to its critical role in maintaining guanine nucleotide pools necessary for DNA and RNA synthesis, GMPS is a significant therapeutic target in oncology, where it is often upregulated to support the rapid proliferation of cancer cells (biorxiv.org, 1.3.3). It is also a validated target for antimicrobial and antiparasitic therapies, particularly against pathogens like Plasmodium falciparum and Mycobacterium tuberculosis (mdpi.com, 1.3.2). Drugs such as mizoribine and decoyinine inhibit GMPS activity, leading to nucleotide depletion and subsequent cell cycle arrest or apoptosis (nih.gov, 1.3.1). Furthermore, GMPS is involved in the metabolic activation of thiopurine prodrugs like 6-mercaptopurine, making its activity a key determinant of drug efficacy and the development of resistance (nih.gov, 1.1.5).

Other names

GMP synthase [glutamine-hydrolyzing]Guanine monophosphate synthaseGuanine monophosphate synthetaseGuanosine 5'-monophosphate synthaseXanthosine 5'-phosphate amidotransferaseGATD7Glutamine amidotransferase

Inhibition of GMPS prevents the conversion of xanthosine 5'-monophosphate (XMP) to guanosine 5'-monophosphate (GMP), leading to the depletion of intracellular guanine nucleotide pools (GMP, GDP, and GTP). This depletion impairs DNA and RNA synthesis, inhibits cell proliferation, and can induce apoptosis in rapidly dividing cells such as cancer cells or pathogens. Additionally, GMPS is required for the metabolic activation of thiopurine drugs like 6-mercaptopurine into active thioguanine nucleotides.