GMP synthase [glutamine-hydrolyzing] (GMPS)

GMP synthase [glutamine-hydrolyzing] (GMPS) is a key metabolic enzyme that catalyzes the final step in the de novo purine biosynthesis pathway, specifically the ATP-dependent conversion of xanthosine 5'-monophosphate (XMP) to guanosine 5'-monophosphate (GMP) using glutamine as a nitrogen donor [1, 14, 17]. This enzyme is essential for maintaining cellular pools of guanine nucleotides, which are critical for DNA and RNA synthesis, signal transduction, and energy metabolism [1, 3]. GMPS is frequently overexpressed in various malignancies, including prostate cancer, melanoma, and leukemias, where it supports the high metabolic requirements of rapidly proliferating cells [4, 5, 13]. Additionally, it is a validated target in numerous pathogenic organisms, such as Plasmodium falciparum and Candida albicans, because its inhibition leads to guanine auxotrophy and reduced virulence [1, 15, 19]. Beyond its catalytic activity, GMPS performs non-metabolic 'moonlighting' functions in the nucleus, such as stabilizing the tumor suppressor p53 and activating the protease USP7, thereby coordinating nucleotide availability with cell cycle regulation [1, 13, 19]. Therapeutic targeting of GMPS typically involves glutamine analogs or nucleoside antibiotics like decoyinine that deplete the guanine pool to induce growth arrest [6, 9].

Other names

Guanine monophosphate synthaseGMP synthetaseGlutamine amidotransferaseGATD7GUAAGuanosine 5'-monophosphate synthase

Inhibition of the ATP-dependent conversion of xanthosine 5'-monophosphate (XMP) to guanosine 5'-monophosphate (GMP), leading to depletion of the guanine nucleotide pool and subsequent arrest of DNA and RNA synthesis.