The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

Abstract

Biotin is the major cofactor involved in carbon dioxide metabolism. Indeed, biotindependent enzymes are ubiquitous in nature and are involved in a myriad of metabolic processes including fatty acid synthesis and gluconeogenesis. The cofactor, itself, is composed of a ureido ring, a tetrahydrothiophene ring, and a valeric acid side chain. It is the ureido ring that functions as the CO 2 carrier. A complete understanding of biotin-dependent enzymes is critically important for translational research in light of the fact that some of these enzymes serve as targets for antiobesity agents, antibiotics, and herbicides. Prior to 1990, however, there was a dearth of information regarding the molecular architectures of biotin-dependent enzymes. In recent years there has been an explosion in the number of three-dimensional structures reported for these proteins. Here we review our current understanding of the structures and functions of biotindependent enzymes. In addition, we provide a critical analysis of what these structures have and have not revealed about biotin-dependent catalysis.

A New Analytical Method for Direct Measurement of Particulate and Dissolved B-vitamins and Their Congeners in Seawater

“…In addition to the primary target analytes listed above, this method can be used to quantify riboflavin (B 2 ), pyridoxal (B 6 ), and the amino acid methionine (Met). Taken together, these analytes represent different active forms and precursors of an important subset of B-vitamins, which have essential biochemical roles in central and secondary metabolic pathways across all domains of life (Begley et al, 1999;Brown, 2005;Waldrop et al, 2012). This method simultaneously measures the particulate and dissolved pools of chemically and functionally diverse B-vitamins that are commonly required by marine microbes, thus enabling novel insights into the ways that B-vitamins impact marine microbial community structure and production.…”

Crystal structure of the essential biotin‐dependent carboxylase AccA3 from Mycobacterium tuberculosis

“…In subunit A the protein chain could be traced from residues 10–465 with the exception of the glycine‐rich T‐loop connecting β‐strands two and three of the B‐domain comprising residues 173–177 (GGGKG). The T‐loop is a conserved feature and commonly observed to be disordered in the absence of bound nucleotide but orders upon nucleotide binding by interactions with the nucleotide phosphate groups 26, 40. The C‐terminal domain of AccA3, expected to mediate the interaction with the AccD subunit 41, 42, was not located in the electron density for any of the monomers.…”

“…Together, the most likely interpretation of the combined structural data of biotin‐dependent carboxylases is that the B‐domain is dynamic over a continuum of conformations, or several defined conformations. This is of interest as it is presently unclear in what state the B‐domain resides in solution, in preparation for nucleotide binding 26. Calculations support a closed or a semiclosed state in solution 45, 46.…”

“…Here, we present the 1.94 Å structure of a full‐length construct of MTb AccA3. As predicted from sequence, AccA3 adopts the three‐domain ATP‐grasp superfamily fold 25, 26. The protein crystallized as a dimer in the asymmetric unit with the monomers displaying different structural states, showing conformational dynamics between domains.…”

The cyclic keto-enol insecticide spirotetramat inhibits insect and spider mite acetyl-CoA carboxylases by interfering with the carboxyltransferase partial reaction

“…Carboxybiotin transfers the carboxyl group to the acceptor substrate, acetyl-CoA (Tong, 2005;Waldrop et al, 2012).…”