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Biosynthesis of t-Butyl in Apratoxin A: Functional Analysis and Architecture of a PKS Loading Module.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2018 Jun 15; Vol. 13 (6), pp. 1640-1650. Date of Electronic Publication: 2018 May 08. - Publication Year :
- 2018
-
Abstract
- The unusual feature of a t-butyl group is found in several marine-derived natural products including apratoxin A, a Sec61 inhibitor produced by the cyanobacterium Moorea bouillonii PNG 5-198. Here, we determine that the apratoxin A t-butyl group is formed as a pivaloyl acyl carrier protein (ACP) by AprA, the polyketide synthase (PKS) loading module of the apratoxin A biosynthetic pathway. AprA contains an inactive "pseudo" GCN5-related N-acetyltransferase domain (ΨGNAT) flanked by two methyltransferase domains (MT1 and MT2) that differ distinctly in sequence. Structural, biochemical, and precursor incorporation studies reveal that MT2 catalyzes unusually coupled decarboxylation and methylation reactions to transform dimethylmalonyl-ACP, the product of MT1, to pivaloyl-ACP. Further, pivaloyl-ACP synthesis is primed by the fatty acid synthase malonyl acyltransferase (FabD), which compensates for the ΨGNAT and provides the initial acyl-transfer step to form AprA malonyl-ACP. Additionally, images of AprA from negative stain electron microscopy reveal multiple conformations that may facilitate the individual catalytic steps of the multienzyme module.
- Subjects :
- Acyl Carrier Protein metabolism
Amino Acid Sequence
Bacterial Proteins chemistry
Carboxy-Lyases chemistry
Catalytic Domain
Cyanobacteria chemistry
Decarboxylation
Depsipeptides chemistry
Depsipeptides isolation & purification
Methylation
Methyltransferases chemistry
Multifunctional Enzymes chemistry
Polyketide Synthases chemistry
Substrate Specificity
Bacterial Proteins metabolism
Carboxy-Lyases metabolism
Depsipeptides biosynthesis
Methyltransferases metabolism
Multifunctional Enzymes metabolism
Polyketide Synthases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 13
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 29701944
- Full Text :
- https://doi.org/10.1021/acschembio.8b00252