Acetyl-CoA carboxylase from Escherichia coli exhibits a pronounced hysteresis when inhibited by palmitoyl-acyl carrier protein

Acetyl-CoA carboxylase (ACC) in bacteria is composed of three components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. ACC catalyzes the first committed step in fatty acid synthesis: the carboxylation of acetyl-CoA to form malonyl-CoA via a two-step reaction. In the...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2017-12, Vol.636, p.100-109
Main Authors: Evans, Alexandra, Ribble, Wendy, Schexnaydre, Erin, Waldrop, Grover L.
Format: Article
Language:English
Subjects:
ACC- acetyl-CoA carboxylase
ACP- acyl carrier protein
BC- biotin carboxylase
BCCP- biotin carboxyl carrier protein
CT- carboxyltransferase
PACP- palmitoyl-acyl carrier protein
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Summary:Acetyl-CoA carboxylase (ACC) in bacteria is composed of three components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. ACC catalyzes the first committed step in fatty acid synthesis: the carboxylation of acetyl-CoA to form malonyl-CoA via a two-step reaction. In the first half-reaction, biotin carboxylase catalyzes the ATP-dependent carboxylation of the vitamin biotin covalently linked to biotin carboxyl carrier protein. In the second half-reaction, the carboxyl group is transferred from biotin to acetyl-CoA by the enzyme carboxyltransferase, to form malonyl-CoA. In most Gram-negative and Gram-positive bacteria, the three components of ACC form a complex that requires communication for catalysis, and is subject to feedback inhibition by acylated-acyl carrier proteins. This study investigated the mechanism of inhibition of palmitoyl-acyl carrier protein (PACP) on ACC. Unexpectedly, ACC was found to exhibit a significant hysteresis, meaning ACC was subject to inhibition by PACP in a time dependent manner. Pull-down assays demonstrated PACP does not prevent formation of the multiprotein complex, while steady-state kinetic analyses showed PACP inhibited ACC activity allosterically. Structure-activity analyses revealed that the pantothenic acid moiety of PACP is responsible for the inhibition of ACC. This study provides the first evidence of the hysteretic nature of ACC. •Acetyl-CoA carboxylase (ACC) exhibits a marked hysteresis when inhibited by palmitoyl-acyl carrier protein (PACP).•Hysteresis of ACC mitigates dramatic oscillations of metabolites in fatty acid synthesis.•PACP acts as an allosteric inhibitor on ACC.•Pantothenic acid is the inhibitory moiety of PACP.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2017.10.016