Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1989 May 1;259(3):921–924. doi: 10.1042/bj2590921

Mechanism of hypoglycaemic action of methylenecyclopropylglycine.

K Melde 1, H Buettner 1, W Boschert 1, H P Wolf 1, S Ghisla 1
PMCID: PMC1138607  PMID: 2730593

Abstract

The effects of methylenecyclopropylglycine (MCPG), the lower homologue of hypoglycin A, on starved rats are described. Upon oral ingestion of MCPG (43 mg/kg), a 50% decrease in blood glucose compared with controls was observed after 4 h. The plasma concentrations of lactate and non-esterified fatty acids were substantially increased during this period. The activity of general acyl-CoA dehydrogenase from isolated rat liver mitochondria was not significantly changed. By contrast, the activity of 2-methyl-(branched-chain)-acyl-CoA dehydrogenase decreased by over 80%. The enzyme activity of enoyl-CoA hydratase (crotonase) from pig kidneys decreased by 80% on incubation with the hypothetically toxic metabolite of MCPG, methylenecyclopropylformyl-CoA. These results suggest that the inhibition spectrum of MCPG is quite different from that of hypoglycin A and that similar physiological effects might result from inhibition of different enzymes of beta-oxidation, e.g. hypoglycaemia and lacticacidemia. Accumulation of medium-chain acyl-CoA thioesters is probably at the origin of disturbances in pyruvate metabolism.

Full text

PDF
921

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. DUNCOMBE W. G. THE COLORIMETRIC MICRO-DETERMINATION OF NON-ESTERIFIED FATTY ACIDS IN PLASMA. Clin Chim Acta. 1964 Feb;9:122–125. doi: 10.1016/0009-8981(64)90004-x. [DOI] [PubMed] [Google Scholar]
  2. Engel P. C., Massey V. Green butyryl-coenzyme A dehydrogenase. An enzyme-acyl-coenzyme A complex. Biochem J. 1971 Dec;125(3):889–902. doi: 10.1042/bj1250889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. GRAY D. O., FOWDEN L. alpha-(Methylenecyclopropyl)glycine from Litchi seeds. Biochem J. 1962 Mar;82:385–389. doi: 10.1042/bj0820385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ghisla S., Thorpe C., Massey V. Mechanistic studies with general acyl-CoA dehydrogenase and butyryl-CoA dehydrogenase: evidence for the transfer of the beta-hydrogen to the flavin N(5)-position as a hydride. Biochemistry. 1984 Jul 3;23(14):3154–3161. doi: 10.1021/bi00309a008. [DOI] [PubMed] [Google Scholar]
  5. HASSALL C. H., REYLE K. Hypoglycin A and B, two biologically active polypeptides from Blighia sapida. Biochem J. 1955 Jun;60(2):334–339. doi: 10.1042/bj0600334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. HASSALL C. H., REYLE K. Hypoglycin A,B: biologically active polypeptides from Blighia sapida. Nature. 1954 Feb 20;173(4399):356–357. doi: 10.1038/173356b0. [DOI] [PubMed] [Google Scholar]
  7. Kean E. A. Selective inhibition of acyl-CoA dehydrogenases by a metabolite of hypoglycin. Biochim Biophys Acta. 1976 Jan 23;422(1):8–14. doi: 10.1016/0005-2744(76)90003-6. [DOI] [PubMed] [Google Scholar]
  8. Lau S. M., Powell P., Buettner H., Ghisla S., Thorpe C. Medium-chain acyl coenzyme A dehydrogenase from pig kidney has intrinsic enoyl coenzyme A hydratase activity. Biochemistry. 1986 Jul 29;25(15):4184–4189. doi: 10.1021/bi00363a003. [DOI] [PubMed] [Google Scholar]
  9. Osmundsen H., Sherratt H. S. A novel mechanism for inhibition of beta-oxidation by methylenecyclopropylacetyl-CoA, a metabolite of hypoglycin. FEBS Lett. 1975 Jul 15;55(1):38–41. doi: 10.1016/0014-5793(75)80951-3. [DOI] [PubMed] [Google Scholar]
  10. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  11. Rhead W. J., Hall C. L., Tanaka K. Novel tritium release assays for isovaleryl-CoA and butyryl-CoA dehydrogenases. J Biol Chem. 1981 Feb 25;256(4):1616–1624. [PubMed] [Google Scholar]
  12. Saggerson E. D., Carpenter C. A. Response to starvation of hepatic carnitine palmitoyltransferase activity and its regulation by malonyl-CoA. Sex differences and effects of pregnancy. Biochem J. 1982 Dec 15;208(3):673–678. doi: 10.1042/bj2080673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Sherratt H. S. Hypoglycin and related hypoglycaemic compounds. Br Med Bull. 1969 Sep;25(3):250–255. doi: 10.1093/oxfordjournals.bmb.a070713. [DOI] [PubMed] [Google Scholar]
  14. Tanaka K. On the mode of action of hypoglycin A. 3. Isolation and identification of cis-4-decene-1,10-dioic, cis, cis-4,7-decadiene-1,10-dioic, cis-4-octene-1,8-dioic, glutaric, and adipic acids, N-(methylenecyclopropyl)acetylglycine, and N-isovalerylglycine from urine of hypoglycin A-treated rats. J Biol Chem. 1972 Dec 10;247(23):7465–7478. [PubMed] [Google Scholar]
  15. Von Holt C. Methylenecyclopropaneacetic acid, a metabolite of hypoglycin. Biochim Biophys Acta. 1966 Aug 3;125(1):1–10. doi: 10.1016/0005-2760(66)90138-x. [DOI] [PubMed] [Google Scholar]
  16. Von Holt C., Von Holt M., Böhm H. Metabolic effects of hypoglycin and methylenecyclopropaneacetic acid. Biochim Biophys Acta. 1966 Aug 3;125(1):11–21. doi: 10.1016/0005-2760(66)90139-1. [DOI] [PubMed] [Google Scholar]
  17. Waterson R. M., Conway R. S. Enoyl-CoA hydratases from Clostridium acetobutylicum and Escherichia coli. Methods Enzymol. 1981;71(Pt 100):421–430. doi: 10.1016/0076-6879(81)71053-x. [DOI] [PubMed] [Google Scholar]
  18. Wenz A., Thorpe C., Ghisla S. Inactivation of general acyl-CoA dehydrogenase from pig kidney by a metabolite of hypoglycin A. J Biol Chem. 1981 Oct 10;256(19):9809–9812. [PubMed] [Google Scholar]
  19. Wolf H. P., Eistetter K., Ludwig G. Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals. Diabetologia. 1982 Jun;22(6):456–463. doi: 10.1007/BF00282590. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES