3-Ketoacyl-ACP synthase (KAS) III homologues and their roles in natural product biosynthesis

Nofiani, Risa; Philmus, Benjamin; Nindita, Yosi; Mahmud, Taifo

doi:10.1039/c9md00162j

“…Citrate (or its O ‐methylated derivative) is proposed to be converted to the corresponding coenzyme A thioester by BolB, which shows similarity to acyl‐CoA synthetases (Figure 3 and Table S4). Either BolM or BolP, both of which show similarity to β‐ketoacyl synthase III (KAS III) enzymes that typically initiate fatty acid biosynthesis in bacteria (Table S4), [26] could then catalyse the elongation of citryl‐CoA (or its O‐methylated derivative) with a malonyl group attached to the primary metabolic fatty acid synthase (FAS) acyl carrier protein (ACP) (Figure 3). Interestingly, the conserved active site Cys residue is mutated to Ser in BolM and Thr in BolP.…”

Section: Resultsmentioning

confidence: 99%

Discovery and Biosynthesis of Bolagladins: Unusual Lipodepsipeptides from Burkholderia gladioli Clinical Isolates**

Dashti

¹

,

Nakou

²

,

Mullins

³

et al. 2020

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Tw oBurkholderia gladioli strains isolated from the lungs of cystic fibrosis patients were found to produce unusual lipodepsipeptides containing aunique citrate-derived fatty acid and ar are dehydro-b-alanine residue.T he gene cluster responsible for their biosynthesis was identified by bioinformatics and insertional mutagenesis.I n-frame deletions and enzyme activity assays were used to investigate the functions of several proteins encoded by the biosynthetic gene cluster,which was found in the genomes of about 45 %ofB.gladioli isolates, suggesting that its metabolic products playanimportant role in the growth and/or survival of the species.T he Chrome Azurol Sa ssayi ndicated that these metabolites bind ferric iron, whichs uppresses their production when added to the growth medium. Moreover,agene encoding aTonB-dependent ferric-siderophore receptor is adjacent to the biosynthetic genes,s uggesting that these metabolites mayf unction as siderophores in B. gladioli.

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“…Citrate (or its O-methylated derivative) is proposed to be converted to the corresponding coenzyme At hioester by BolB,w hich shows similarity to acyl-CoAs ynthetases (Figure 3and Table S4). Either BolM or BolP,both of which show similarity to b-ketoacyls ynthase III (KAS III) enzymes that typically initiate fatty acid biosynthesis in bacteria (Table S4), [26] could then catalyse the elongation of citryl-CoA (or its O-methylated derivative) with am alonyl group attached to the primary metabolic fatty acid synthase (FAS) acyl carrier protein (ACP) (Figure 3). Interestingly,t he conserved active site Cys residue is mutated to Ser in BolM and ThrinBolP.The functional significance of this is unclear, but an analogous Cys to Ser mutation is observed in DpsC, aK AS III homologue that has been reported to initiate assembly of the daunorubicin polyketide chain using ap ropionyl-CoA starter unit.…”

Section: Methodsmentioning

confidence: 99%

Discovery and Biosynthesis of Bolagladins: Unusual Lipodepsipeptides from Burkholderia gladioli Clinical Isolates**

Dashti

¹

,

Nakou

²

,

Mullins

³

et al. 2020

View full text Add to dashboard Cite

Tw oBurkholderia gladioli strains isolated from the lungs of cystic fibrosis patients were found to produce unusual lipodepsipeptides containing aunique citrate-derived fatty acid and ar are dehydro-b-alanine residue.T he gene cluster responsible for their biosynthesis was identified by bioinformatics and insertional mutagenesis.I n-frame deletions and enzyme activity assays were used to investigate the functions of several proteins encoded by the biosynthetic gene cluster,which was found in the genomes of about 45 %ofB.gladioli isolates, suggesting that its metabolic products playanimportant role in the growth and/or survival of the species.T he Chrome Azurol Sa ssayi ndicated that these metabolites bind ferric iron, whichs uppresses their production when added to the growth medium. Moreover,agene encoding aTonB-dependent ferric-siderophore receptor is adjacent to the biosynthetic genes,s uggesting that these metabolites mayf unction as siderophores in B. gladioli.

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“…These constitute a large family of fatty acid and natural product biosynthetic enzymes that catalyze a range of highly diverse reactions. 28 Based on the available substrates for CybF, compounds 16 and 17, we propose an initial decarboxylative O-acylation to give 18 (Figure 4A). Subsequent tethering of 18 to CybF by nucleophilic attack of an active-site residue onto the p-coumaric acid-derived Michael system gives enolate 19.…”

Section: Cybf Catalyzes An Unprecedented Acylation / Cc-bond Formation / Hydride Shift Reaction Cascadementioning

confidence: 95%

(Bio-)Synthesis of the Aquatic Phytotoxin Cyanobacterin – A Paradigm for Furanolide Core Structure Assembly

D’Agostino¹,

Seel²,

Gulder³

et al. 2021

Preprint

1

0

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The gamma-butyrolactone structural motif is commonly found in many natural signaling molecules and other specialized metabolites. A prominent example is the potent aquatic phytotoxin cyanobacterin bearing a highly functionalized gamma-butyrolactone core structure. The enzymatic machinery assembling cyanobacterin and the many structurally related natural products – herein termed furanolides – has remained elusive over decades. Here we discover and characterize the underlying biosynthetic process of furanolide core structure assembly. The cyanobacterin biosynthetic gene cluster (cyb) is identified by targeted bioinformatic screening and validated by heterologous expression in E. coli. Functional evaluation of the recombinant key enzymes provides in-depth mechanistic insights into a streamlined C,C-bond-forming cascade that involves installation of compatible reactivity at seemingly unreactive C-alpha-positions of the amino acid precursors and facilitates development of a one-pot biocatalytic in vitro synthesis. Our work extends the biosynthetic and biocatalytic toolbox for gamma-butyrolactone formation. It thereby provides a general paradigm for the biosynthesis of furanolides and thus sets the stage for their targeted discovery, biosynthetic engineering and enzymatic synthesis.

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3-Ketoacyl-ACP synthase (KAS) III homologues and their roles in natural product biosynthesis

Abstract: KAS III-like enzymes play a significant role in natural product biosynthesis through C–C, C–O, and/or C–N bond formation.

Cited by 46 publications

References 111 publications

Discovery and Biosynthesis of Bolagladins: Unusual Lipodepsipeptides from Burkholderia gladioli Clinical Isolates**

Discovery and Biosynthesis of Bolagladins: Unusual Lipodepsipeptides from Burkholderia gladioli Clinical Isolates**

Discovery and Biosynthesis of Bolagladins: Unusual Lipodepsipeptides from Burkholderia gladioli Clinical Isolates**

(Bio-)Synthesis of the Aquatic Phytotoxin Cyanobacterin – A Paradigm for Furanolide Core Structure Assembly

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