The Conserved Modular Elements of the Acyl Carrier Proteins of Lipid Synthesis Are Only Partially Interchangeable

Zhu, Lei; Cronan, John E.

doi:10.1074/jbc.m115.648402

Cited by 16 publications

(24 citation statements)

References 28 publications

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“…Escherichia coli ACP (called AcpP), the most thoroughly studied member of the ACP family, is an abundant, small, and negatively charged protein that is essential for growth (7–9). Prior work showed that expression of the ACPs from a diverse set of bacteria could replace the function of E.…”

Section: Introductionmentioning

confidence: 99%

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Enterococcus faecalis Encodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

Zhu

Zou

Cao

et al. 2019

mBio

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Acyl carrier proteins (ACPs) play essential roles in the synthesis of fatty acids and transfer of long fatty acyl chains into complex lipids. The Enterococcus faecalis genome contains two annotated acp genes, called acpA and acpB. AcpA is encoded within the fatty acid synthesis (fab) operon and appears essential. In contrast, AcpB is an atypical ACP, having only 30% residue identity with AcpA, and is not essential. Deletion of acpB has no effect on E. faecalis growth or de novo fatty acid synthesis in media lacking fatty acids. However, unlike the wild-type strain, where growth with oleic acid resulted in almost complete blockage of de novo fatty acid synthesis, the ΔacpB strain largely continued de novo fatty acid synthesis under these conditions. Blockage in the wild-type strain is due to repression of fab operon transcription, leading to levels of fatty acid synthetic proteins (including AcpA) that are insufficient to support de novo synthesis. Transcription of the fab operon is regulated by FabT, a repressor protein that binds DNA only when it is bound to an acyl-ACP ligand. Since AcpA is encoded in the fab operon, its synthesis is blocked when the operon is repressed and acpA thus cannot provide a stable supply of ACP for synthesis of the acyl-ACP ligand required for DNA binding by FabT. In contrast to AcpA, acpB transcription is unaffected by growth with exogenous fatty acids and thus provides a stable supply of ACP for conversion to the acyl-ACP ligand required for repression by FabT. Indeed, ΔacpB and ΔfabT strains have essentially the same de novo fatty acid synthesis phenotype in oleic acid-grown cultures, which argues that neither strain can form the FabT-acyl-ACP repression complex. Finally, acylated derivatives of both AcpB and AcpA were substrates for the E. faecalis enoyl-ACP reductases and for E. faecalis PlsX (acyl-ACP; phosphate acyltransferase). IMPORTANCE AcpB homologs are encoded by many, but not all, lactic acid bacteria (Lactobacillales), including many members of the human microbiome. The mechanisms regulating fatty acid synthesis by exogenous fatty acids play a key role in resistance of these bacteria to those antimicrobials targeted at fatty acid synthesis enzymes. Defective regulation can increase resistance to such inhibitors and also reduce pathogenesis.

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Section: Introductionmentioning

confidence: 99%

“…lactis AcpA sequences showed that specific protein sequences located largely in helix II were incompatible with an E. coli lipid synthesis enzyme(s) (9).…”

Section: Introductionmentioning

confidence: 99%

Enterococcus faecalis Encodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

Zhu

Zou

Cao

et al. 2019

mBio

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“…The presence of an amide linkage perturbs residues in helices II and III, while presence of the ester linkage induces these perturbations as well as additional CSPs of residues in helix IV (Figure ). We note that helix II is considered the “recognition helix,” and that AcpP primarily interacts with partner proteins through helices II and III …”

Section: Figurementioning

confidence: 99%

Modifying the Thioester Linkage Affects the Structure of the Acyl Carrier Protein

Sztain

Patel

et al. 2019

Angew Chem Int Ed

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At the center of many complex biosynthetic pathways, the acyl carrier protein (ACP) shuttles substrates to appropriate enzymatic partners to produce fatty acids and polyketides. Carrier proteins covalently tether their cargo via a thioester linkage to a phosphopantetheine cofactor. Due to the labile nature of this linkage, chemoenzymatic methods have been developed that involve replacement of the thioester with a more stable amide or ester bond. We explored the importance of the thioester bond to the structure of the carrier protein by using solution NMR spectroscopy and molecular dynamics simulations. Remarkably, the replacement of sulfur with other heteroatoms results in significant structural changes, thus suggesting more rigorous selections of isosteric substitutes is needed.

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“…It is the rate-limiting step in fatty acid biosynthesis, and is of interest in biofuel development. Despite of its importance in primary metabolism, the atomic details of its dynamics and interactions with AcpP are lacking, hindering bioengineering efforts involving FabB (Chemler et al, 2015;Gajewski et al, 2017;Zhu & Cronan, 2015).…”

Section: 2 Case Studymentioning

confidence: 99%

Computational structural enzymology methodologies for the study and engineering of fatty acid synthases, polyketide synthases and nonribosomal peptide synthetases

Schaub

Moreno

Zhao

et al. 2019

Methods in Enzymology

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Various computational methodologies can be applied to enzymological studies on enzymes in the fatty acid, polyketide, and non-ribosomal peptide biosynthetic pathways. These multi-domain complexes are called fatty acid synthases, polyketide synthases, and non-ribosomal peptide synthetases. These mega-synthases biosynthesize chemically diverse and complex bioactive molecules, with the intermediates being chauffeured between catalytic partners via a carrier *

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The Conserved Modular Elements of the Acyl Carrier Proteins of Lipid Synthesis Are Only Partially Interchangeable

Cited by 16 publications

References 28 publications

Enterococcus faecalis Encodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

Enterococcus faecalis Encodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

Modifying the Thioester Linkage Affects the Structure of the Acyl Carrier Protein

Computational structural enzymology methodologies for the study and engineering of fatty acid synthases, polyketide synthases and nonribosomal peptide synthetases

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