The pleiotypic response to amino acid deprivation is the result of interactions between components of the glycolysis and protein synthesis pathways.
Several diverse metabolic events become compromised when mammalian cells are made deficient in essential amino acids or when charging of their tRNA is blocked by amino acid analogs. This rapid general demise of cell function can be due to inhibition of phosphofructokinase (PFK) by uncharged tRNA. It has now been demonstrated that when tRNA is added to PFK in an assay dependent upon the reassociation of inactive, dissociated enzyme subunits, nanomolar concentrations cause complete inhibition. The model for control suggests that charged tRNA becomes associated with EF-1, which is specific for aminoacyl-tRNAs and is present in sufficiently high concentrations in cells to sequester that charged forms from an inhibitory role. Support for this model include: (1) the rapid onset of inhibition of glycolysis and glucose uptake upon amino acid deficiency; (2) the unique role of the product of PFK activity, fructose-1,6-diphosphate, in reactions of peptide chain initiation, particularly its role as a co-factor for purified eIF-2B, the GDP/GTP exchange factor; (3) the correlations of this interaction with the cellular and molecular lesions of insulin insufficiency; (4) the recognition that the anomalous role of high concentrations of cAMP as a stimulant of peptide chain initiation in energy depleted or gel-filtered cell lysates correlates with its stimulatory action on PFK as an analog for the positive effector, adenosine-5'-monophosphate; and (5) the role of fructose-1,6-diphosphate in the formation of glyceraldehyde-3-phosphate, a substrate for synthesis of ribose-5-phosphate via the non-oxidative portion of the pentose phosphate pathway, which, as a precursor of phosphoribosylpyrophosphate, is essential for nucleic acid synthesis.
Rabinovitz
M
M
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
D000596:Amino Acids / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D004734:Energy Metabolism; D005635:Fructosediphosphates / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D008954:Models, Biological; D009132:Muscles / Q000201:enzymology; D009696:Nucleic Acids / Q000096:biosynthesis; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D012360:RNA, Transfer, Phe / Q000494:pharmacology; D011817:Rabbits
D000596:Amino Acids; D005635:Fructosediphosphates; D007328:Insulin; D009696:Nucleic Acids; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors; D012346:RNA, Transfer, Amino Acyl; D012360:RNA, Transfer, Phe; D006160:Guanosine Triphosphate; D000242:Cyclic AMP; D010732:Phosphofructokinase-1; C029063:fructose-1,6-diphosphate