Summary
The sulfur atom in the vitamin biotin has previously been suggested to be essential in biotin's mechanism of action. In a series of investigations on structure-function relationships with biotin analogs not containing the sulfur atom, the biotin analogs, azabiotin, bisnorazabiotin, carbobiotin and isoazabiotin enhanced guanylate cyclase, an enzyme that has recently been demonstrated to be activated by biotin. These analogs increased guanylate cyclase activity two-fold in liver, cerebellum, heart, kidney and colon at 1 μM concentrations. The ED50 for stimulation of guanulate cyclase activity occurred at 0.1 μM for each of the biotin analogs. These data indicate that the sulfur atom is not essential in biotin's activation of guanylate cyclase since these analogs do not contain the sulfur atom. Studies on the ring structure of biotin revealed that even compounds with a single 5-membered ring (2-imidazolidone) could augment guanylate cyclase activity. The guanylate cyclase co-factor manganese was not essential for the enhancement of guanylate cyclase by these agents but a maximal activation of this enzyme by these analogs could not be obtained without manganese present.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Kogl F, Tennis B: Uber das Bios-Problem. Darstellung von krystallisiertem Biotin aus Eigelb. Z Physiol Chem 42:43–73, 1936.
Du Vigneaud V, Hofmann K, Melville DB: On the structure of biotin. J Am Chem Soc 64:188–189, 1942.
Harris SA, Wolf DE, Mozingo R, Folkers K: Synthetic biotin. Science 97:447–448, 1942.
Mildvan AS, Scrutton MC, Utter ME: Pyruvate carboxylase. J Biol Chem 41:3488–3498, 1966.
Bowen CE, Rauscher E, Ingraham LL: The basicity of biotin. Arch Biochem Biophys 125:865–872, 1968.
Sigel H, McCormick DB, Griesser R, Prijis B, Wright LD: Metal ion complexes with biotin and biotin derivatives. Participation of sulfur in the orientation of divalent cations. Biochemistry 8:2687–2695, 1969.
Wormser HC, Israsena S, Meiling MS, Williams C, Perlman D: Synthesis and growth-promoting activity of dl-cis hexahydro-4-(4-carboxybutyl)-2-cyclopentimidazolone: carbobiotin. J Pharm Sci 61:1168–1170, 1972.
WormserH C, Abramson HN: Synthesisofdl-4ε-(2-carboxyethyl)-cis-hexa-hydropyrrolo-[3,4-d]-imidazol-2-one (bisnorazabiotin). J Pharm Sci 64: 1882–1884, 1975.
Wormser HC, Abramson HN: New compounds: total synthesis of dl-3a,4,6a-cis-4-(4-carboxybutyl)-hexahydropyrrolo-[3,4-d]-imidazol-2-one hydrochloride (dl-azabiotin hydrochloride). J Pharm Sci 66:1208–1210, 1977.
Vesely DL: Biotin enhances guanylate cyclase activity. Science 216:1329–1330, 1982.
Vesely DL: Testosterone and its precursors and metabolites enhance guanylate cyclase activity. Proc Natl Acad Sci USA 76:3491–3494, 1979.
Vesely DL: Angiotensin 11 stimulates guanylate cyclase activity in aorta, heart and kidney. Am J Physiol 240:E391-E393, 1981.
Vesely DL, Rovere LE, Levey GS: Activation of guanylate cyclase by streptozotocin and 1-methyl-I-nitrosourea. Cancer Res 37:28–31, 1977.
Boeck RL, Dakshinamurti K: Effect of biotin on ribonucleic acid synthesis. Biochim Biophys Acta 383:282–289, 1975.
Boeck RL, Dakshinamurti K: Biotin-mediated protein biosynthesis. Biochem J 140:549–556, 1974.
Goldberg ND, Haddox MK, Dunham E, Lopez C, Hadden JW: The yin yang hypothesis of biological control: opposing influences of cyclic GMP and cyclic AMP in the regulation of cell proliferation in animal cells. In: B Clarkson and R Baserga (eds). Control of Proliferation in Animal Cells. Cold Springs Harbor Laboratory, New York, 1974, pp 609–625.
Paulus H, Sarkar N: Control of transcription in Bacillus brevis by small molecules. Basic Life Sci 3:21–34, 1974.
Varrone S, DiLauro R, Macchia V: Stimulation of polypeptide synthesis by cyclic 3′,5′-guanosine monophosphate. Arch Biochem Biophys 157:334–338, 1973.
Watson J, Epstein R, Cohn M: Cyclic nucleotides as intracellular mediators of the expression of antigen-sensitive cells. Nature 246:405–409, 1973.
Vesely DL: Human and rat growth hormones enhance guanylate cyclase activity. Am J Physiol 240:E79-E81, 1981.
Vesely DL: Rochat ML: Gibberellic acid, a plant growth hormone, enhances mammalian guanylate cyclase activity. Res Commun Chem Pathol Pharmacol 28:123–132, 1980.
Rudland PS, Gospodarowicz D, Seifert W: Activation of guanyl cyclase and intracellular cyclic GMP by fibroblast growth factor. Nature 250:741–742, 773–774, 1974.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vesely, D.L., Wormser, H.C. & bramson, H.N. Biotin analogs activate guanylate cyclase. Mol Cell Biochem 60, 109–114 (1984). https://doi.org/10.1007/BF00222480
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00222480