Modeling and numerical simulation of biotin carboxylase kinetics: implications for half-sites reactivity.

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de Queiroz MS, Waldrop GL

Modeling and numerical simulation of biotin carboxylase kinetics: implications for half-sites reactivity.

J Theor Biol. 2007 May 7;246(1):167-75. Epub 2006 Dec 28.

PubMed ID

17266990 [ View in PubMed

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Abstract

Biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase that catalyzes the first committed step in fatty acid synthesis in all organisms. In Escherichia coli, biotin carboxylase exists as a homodimer where each subunit contains a complete active site. In a previous study (Janiyani, K., Bordelon, T., Waldrop, G.L., Cronan Jr., J.E., 2001. J. Biol. Chem. 276, 29864-29870), hybrid dimers were constructed where one subunit was wild-type and the other contained an active site mutation that reduced activity at least 100-fold. The activity of the hybrid dimers was only slightly greater than the activity of the mutant homodimers and far less than the expected 50% activity for completely independent active sites. Thus, there is communication between the two subunits of biotin carboxylase. The dominant negative effect of the mutations on the wild-type active site was interpreted as alternating catalytic cycles of the active sites in the homodimer. In order to test the hypothesis of oscillating catalytic cycles, mathematical modeling and numerical simulations of the kinetics of wild-type, hybrid dimers, and mutant homodimers of biotin carboxylase were performed. Numerical simulations of biotin carboxylase kinetics were the most similar to the experimental data when an oscillating active site model was used. In contrast, alternative models where the active sites were independent did not agree with the experimental data. Thus, the numerical simulations of the proposed kinetic model support the hypothesis that the two active sites of biotin carboxylase alternate their catalytic cycles.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Biotin	Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial	Protein	Humans	Unknown	Cofactor	Details