Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Escherichia coli the enzyme guanosine kinase phosphorylates guanosine to GMP, which is further phosphorylated to GDP and GTP by other enzymes. Here I report that guanosine kinase is subject to efficient feedback inhibition by the end product of the pathway, GTP, and that this regulation is abolished by a previously described mutation, gsk-3, in the structural gene for guanosine kinase (Hove-Jensen, B., and Nygaard, P. (1989) J. Gen. Microbiol. 135, 1263-1273). Consequently, the gsk-3 mutant strain was extremely sensitive to guanosine, which caused the guanine nucleotide pools to increase dramatically, thereby initiating a cascade of metabolic changes that eventually led to growth arrest. By isolation and characterization of guanosine-resistant derivatives of the gsk-3 mutant, some of the crucial steps in this deleterious cascade of events were found to include the following: first, conversion of GMP to adenine nucleotides via GMP reductase, encoded by the guaC gene; second, inhibition of phosphoribosylpyrophosphate synthetase by an adenine nucleotide, presumably ADP, causing starvation for histidine, tryptophan, and pyrimidines, all of which require PRPP for their synthesis; third, accumulation of the regulatory nucleotide guanosine 5',3'-bispyrophosphate (ppGpp), a general transcriptional inhibitor synthesized by the relA gene product in response to amino acid starvation.
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PMID:Inhibition of cellular growth by increased guanine nucleotide pools. Characterization of an Escherichia coli mutant with a guanosine kinase that is insensitive to feedback inhibition by GTP. 1002 43

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyses the rate-limiting step in guanine nucleotide biosynthesis. IMPDH has an evolutionary conserved CBS subdomain of unknown function. The subdomain can be deleted without impairing the in vitro IMPDH catalytic activity and is the site for mutations associated with human retinitis pigmentosa. A guanine-prototrophic Escherichia coli strain, MP101, was constructed with the subdomain sequence deleted from the chromosomal gene for IMPDH. The ATP content was substantially elevated in MP101 whereas the GTP content was slighty reduced. The activities of IMPDH, adenylosuccinate synthetase and GMP reductase were two to threefold lower in MP101 crude extracts compared with the BW25113 wild-type strain. Guanine induced a threefold reduction in the MP101 ATP pool and a fourfold increase in the GTP pool within 10 min of addition to growing cells; this response does not result from the reduced IMPDH activity or starvation for guanylates. In vivo kinetic analysis using 14-C tracers and 33-P pulse-chasing revealed mutation-associated changes in purine nucleotide fluxes and turnover rates. We conclude that the CBS subdomain of IMPDH may coordinate the activities of the enzymes of purine nucleotide metabolism and is essential for maintaining the normal ATP and GTP pool sizes in E. coli.
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PMID:The CBS subdomain of inosine 5'-monophosphate dehydrogenase regulates purine nucleotide turnover. 1831 63