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Review
. 2021 Aug 18;85(3):e0003221.
doi: 10.1128/MMBR.00032-21. Epub 2021 Jun 16.

The Classical, Yet Controversial, First Enzyme of Lipid Synthesis: Escherichia coli Acetyl-CoA Carboxylase

John E Cronan  1   2
Affiliations
Review

The Classical, Yet Controversial, First Enzyme of Lipid Synthesis: Escherichia coli Acetyl-CoA Carboxylase

John E Cronan. Microbiol Mol Biol Rev. .

Abstract

Escherichia coli acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, the building block of fatty acid synthesis, is the paradigm bacterial ACC. Many reports on the structures and stoichiometry of the four subunits comprising the active enzyme as well as on regulation of ACC activity and expression have appeared in the almost 20 years since this subject was last reviewed. This review seeks to update and expand on these reports.

Keywords: acetyl-CoA; biotin; carboxylase; fatty acid synthesis; malonyl-CoA.

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Figures

FIG 1
FIG 1
The ACC reaction and biotin attachment to apo AccB. The acetyl-CoA carboxylase and BirA biotin protein ligase reactions. Panel A shows the acetyl-CoA carboxylase reaction, whereas panel B shows the BirA reaction, which is the general reaction of biotin protein ligases. Apo AccB is the primary translation product folded into the structure given in Fig. 2 but lacking the amide linked biotin moiety (lysine 122 has a free ε-amino group in the apo form). (Reproduced from reference .)
FIG 2
FIG 2
Crystal structurers of AccB (PDB 1BDO), AccC (PDB 4HR7), and the AccA-AccD dimer of dimers (PDB 2F9Y). (A) The 1.8-Å structure of the AccB biotin domain. The AccB “thumb” domain is essential for activity and is characteristic of bacterial and plastid AccB proteins (24). The thumb interacts with the biotin moiety (PDB 1BDO) (81). Two AccB biotin domain structures obtained by nuclear magnetic resonance technique, PDB 2BDO (82) and PDB 1A6X (83), are in good agreement with the crystal structure and show that the unbiotinylated and biotinylated forms have essentially the same structure, although the structure tightens upon biotinylation (83–85). The NMR reports also demonstrate the disordered nature of the residues N-terminal to the biotin domain. (B) The 2.4-Å structure of the AccC dimer that catalyzes carboxylation of the biotin moiety of AccB (20). The “flaps” to the left (upper monomer) or right (lower monomer) close over the ATP molecules (PDB 1DV2) (86). This movement is characteristic of the Mg2+-ATP grasp protein family which includes numerous ligases. (C) The 3.2-Å structure of the AccA-AccD dimer of dimers that catalyzes transfer of the carboxyl moiety of carboxybiotinyl AccB to acetyl-CoA to form malonyl-CoA (21). The N-terminal zinc-binding domain of AccD is essential for activity (58, 62) but is not required for assembly of the AccA-AccD dimer of dimers (62). The Zn domain found only in bacterial carboxyltransferases may provide partial protection for bound acetyl-CoA (21).
FIG 3
FIG 3
Cartoon of the overall ACC reaction based on the 2AccA-4AccB-2AccC-2AccD stoichiometry. The AccB-AccC and AccA-AccD complexes are sufficiently stable for isolation in vitro and their partial reactions can be assayed directly. Note that the two AccA-AccD representations would form the 2AccC-2AccD heterotetramer behind the plane of the page.
FIG 4
FIG 4
The biotin regulatory system of E. coli. The bioABFCD operon has two divergent promoters controlled by a common overlapping operator. BirA is represented by green ovals, biotin by black dots, the AMP moiety by red pentagons, AccB by puce ovals, and AccC by blue cutout cans. The arrows denote transcription from the leftward and rightward bio promoters. (A to C) BirA switches from function in biotin ligation to repressor function in response to the intracellular biotin requirement indicated by the level of unbiotinylated AccB. When unbiotinylated AccB levels are high, the protein functions as a biotin ligase and transcription of the bio operon is derepressed, resulting in increased levels of the biosynthesis enzymes and of biotin. Once the unbiotinylated AccB has been converted to the biotinylated form, biotinoyl-5′-AMP is no longer consumed and remains bound to BirA. The dimeric biotinoyl-5′-AMP liganded form of BirA accumulates to levels sufficiently high that the bio operator is fully occupied, resulting in transcriptional repression of the biotin biosynthetic genes. (D) Overproduced AccC ties up unbiotinylated AccB into a complex that is a poor biotinylation substrate. Therefore, high levels of the dimeric biotinoyl-5′-AMP liganded form of BirA accumulate which result in repression of bio operon transcription. (Adapted from reference .)
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