Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1971 Jan;68(1):20–24. doi: 10.1073/pnas.68.1.20

Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Kay Tanaka 1, Edith M Miller 1, Kurt J Isselbacher 1
PMCID: PMC391092  PMID: 5276292

Abstract

Evidence is presented for the specific in vivo and in vitro inhibition of isovaleryl CoA dehydrogenation by hypoglycin A and its derivative, α-ketomethylenecyclopropylpropionic acid. α-Methylbutyryl CoA dehydrogenation was also impaired, but the degree of inhibition was much lower. Isobutyryl CoA dehydrogenation was not inhibited. 4-Pentenoic acid inhibited none of these reactions. It is concluded that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase, contrary to previous assumptions that it is dehydrogenated by green acyl CoA dehydrogenase. The present concept agrees with our previous findings in isovaleric acidemia, a genetic disorder in which a specific defect of isovaleryl CoA dehydrogenase was observed. It was also demonstrated that isovaleric acidemia can be induced in experimental animals by the administration of hypoglycin A. Furthermore, some symptoms of “the vomiting sickness of Jamaica” appear to be due to isovaleric acid accumulation secondary to the ingestion of hypoglycin A.

Full text

PDF
20

Selected References

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

  1. BACHHAWAT B. K., ROBINSON W. G., COON M. J. Enzymatic carboxylation of beta-hydroxyisovaleryl coenzyme A. J Biol Chem. 1956 Apr;219(2):539–550. [PubMed] [Google Scholar]
  2. Brendel K., Corredor C. F., Bressler R. The effect of 4-pentenoic acid on fatty acid oxidation. Biochem Biophys Res Commun. 1969 Feb 7;34(3):340–347. doi: 10.1016/0006-291x(69)90838-9. [DOI] [PubMed] [Google Scholar]
  3. Budd M. A., Tanaka K., Holmes L. B., Efron M. L., Crawford J. D., Isselbacher K. J. Isovaleric acidemia. Clinical features of a new genetic defect of leucine metabolism. N Engl J Med. 1967 Aug 17;277(7):321–327. doi: 10.1056/NEJM196708172770701. [DOI] [PubMed] [Google Scholar]
  4. CHEN K. K., ANDERSON R. C., McCOWEN M. C., HARRIS P. N. Pharmacologic action of hypoglycin A and B. J Pharmacol Exp Ther. 1957 Nov;121(3):272–285. [PubMed] [Google Scholar]
  5. Corredor C., Brendel K., Bressler R. Effects of 4-pentenoic acid on carbohydrate metabolism in pigeon liver homogenate. J Biol Chem. 1969 Mar 10;244(5):1212–1219. [PubMed] [Google Scholar]
  6. Corredor C., Brendel K., Bressler R. Studies of the mechanism of the hypoglycemic action of 4-pentenoic acid. Proc Natl Acad Sci U S A. 1967 Dec;58(6):2299–2306. doi: 10.1073/pnas.58.6.2299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Entman M., Bressler R. The mechanism of action of hypoglycin on long-chain fatty acid oxidation. Mol Pharmacol. 1967 Jul;3(4):333–340. [PubMed] [Google Scholar]
  8. FENG P. C., PATRICK S. J. Studies of the action of hypoglycin-A, an hypoglycaemic substance. Br J Pharmacol Chemother. 1958 Jun;13(2):125–130. doi: 10.1111/j.1476-5381.1958.tb00206.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. GREEN D. E., MII S., MAHLER H. R., BOCK R. M. Studies on the fatty acid oxidizing system of animal tissues. III. Butyryl coenzyme A dehydrogenase. J Biol Chem. 1954 Jan;206(1):1–12. [PubMed] [Google Scholar]
  10. 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]
  11. HILL K. R., BRAS G., CLEARKIN K. P. Acute toxic hypoglycaemia occurring in the vomiting sickness of Jamaica; morbid anatomical aspects. West Indian Med J. 1955 Jun;4(2):91–104. [PubMed] [Google Scholar]
  12. JELLIFFE D. B., STUART K. L. Acute toxic hypoglycaemia in the vomiting sickness of Jamaica. Br Med J. 1954 Jan 9;1(4853):75–77. doi: 10.1136/bmj.1.4853.75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Newman C. G., Wilson B. D., Callaghan P., Young L. Neonatal death associated with isovalericacidaemia. Lancet. 1967 Aug 26;2(7513):439–442. doi: 10.1016/s0140-6736(67)90854-9. [DOI] [PubMed] [Google Scholar]
  14. Posner B. I., Raben M. S. Inhibition of the oxidation of leucine by hypoglycin. Biochim Biophys Acta. 1967 Feb 7;136(1):179–181. doi: 10.1016/0304-4165(67)90341-8. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Tanaka K., Budd M. A., Efron M. L., Isselbacher K. J. Isovaleric acidemia: a new genetic defect of leucine metabolism. Proc Natl Acad Sci U S A. 1966 Jul;56(1):236–242. doi: 10.1073/pnas.56.1.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Tanaka K., Isselbacher K. J. The isolation and identification of N-isovalerylglycine from urine of patients with isovaleric acidemia. J Biol Chem. 1967 Jun 25;242(12):2966–2972. [PubMed] [Google Scholar]
  18. Tanaka K., Orr J. C., Isselbacher K. J. Identification of beta-hydroxyisovaleric acid in the urine of a patient with isovaleric acidemia. Biochim Biophys Acta. 1968 May 1;152(3):638–641. doi: 10.1016/0005-2760(68)90107-0. [DOI] [PubMed] [Google Scholar]
  19. VON HOLT, CHANG J., VON HOLT, BOEHM H. METABOLISM AND METABOLIC EFFECTS OF HYPOGLYCIN. Biochim Biophys Acta. 1964 Sep 4;90:611–613. doi: 10.1016/0304-4165(64)90242-9. [DOI] [PubMed] [Google Scholar]
  20. 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]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES