Dataset Information

Structural characterization of β-ketoacyl ACP synthase I bound to platencin and fragment screening molecules at two substrate binding sites.

ABSTRACT: The bacterial fatty acid pathway is essential for membrane synthesis and a range of other metabolic and cellular functions. The β-ketoacyl-ACP synthases carry out the initial elongation reaction of this pathway, utilizing acetyl-CoA as a primer to elongate malonyl-ACP by two carbons, and subsequent elongation of the fatty acyl-ACP substrate by two carbons. Here we describe the structures of the β-ketoacyl-ACP synthase I from Brucella melitensis in complex with platencin, 7-hydroxycoumarin, and (5-thiophen-2-ylisoxazol-3-yl)methanol. The enzyme is a dimer and based on structural and sequence conservation, harbors the same active site configuration as other β-ketoacyl-ACP synthases. The platencin binding site overlaps with the fatty acyl compound supplied by ACP, while 7-hydroxyl-coumarin and (5-thiophen-2-ylisoxazol-3-yl)methanol bind at the secondary fatty acyl binding site. These high-resolution structures, ranging between 1.25 and 1.70 å resolution, provide a basis for in silico inhibitor screening and optimization, and can aid in rational drug design by revealing the high-resolution binding interfaces of molecules at the malonyl-ACP and acyl-ACP active sites.

SUBMITTER: Patterson EI

PROVIDER: S-EPMC9518911 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Structural characterization of β-ketoacyl ACP synthase I bound to platencin and fragment screening molecules at two substrate binding sites.

Patterson Edward I EI Nanson Jeffrey D JD Abendroth Jan J Bryan Cassie C Sankaran Banumathi B Myler Peter J PJ Forwood Jade K JK

Proteins 20190717 1

The bacterial fatty acid pathway is essential for membrane synthesis and a range of other metabolic and cellular functions. The β-ketoacyl-ACP synthases carry out the initial elongation reaction of this pathway, utilizing acetyl-CoA as a primer to elongate malonyl-ACP by two carbons, and subsequent elongation of the fatty acyl-ACP substrate by two carbons. Here we describe the structures of the β-ketoacyl-ACP synthase I from Brucella melitensis in complex with platencin, 7-hydroxycoumarin, and ( ...[more]

PMID: 31237717

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Project description:Background and aimsThe processes of gene duplication, followed by divergence and selection, probably underpin the evolution of floral volatiles crucial to plant-insect interactions. The Australian sexually deceptive Chiloglottis orchids use a class of 2,5-dialkylcyclohexan-1,3-dione volatiles or 'chiloglottones' to attract specific male wasp pollinators. Here, we explore the expression and evolution of fatty acid pathway genes implicated in chiloglottone biosynthesis.MethodsBoth Chiloglottis seminuda and C. trapeziformis produce chiloglottone 1, but only the phylogenetically distinct C. seminuda produces this volatile from both the labellum callus and glandular sepal tips. Transcriptome sequencing and tissue-specific contrasts of the active and non-active floral tissues was performed. The effects of the fatty acid synthase inhibitor cerulenin on chiloglottone production were tested. Patterns of selection and gene evolution were investigated for fatty acid pathway genes.Key resultsTissue-specific differential expression of fatty acid pathway transcripts was evident between active and non-active floral tissues. Cerulenin significantly inhibits chiloglottone 1 production in the active tissues of C. seminuda. Phylogenetic analysis of plant β-ketoacyl synthase I (KASI), a protein involved in fatty acid biosynthesis, revealed two distinct clades, one of which is unique to the Orchidaceae (KASI-2B). Selection analysis indicated a strong signal of positive selection at the split of KASI-2B followed by relaxed purifying selection in the Chiloglottis clade.ConclusionsBy capitalizing on a phylogenetically distinct Chiloglottis from earlier studies, we show that the transcriptional and biochemical dynamics linked to chiloglottone biosynthesis in active tissues are conserved across Chiloglottis. A combination of tissue-specific expression and relaxed purifying selection operating at specific fatty acid pathway genes may hold the key to the evolution of chiloglottones.

Dataset Information

Structural characterization of β-ketoacyl ACP synthase I bound to platencin and fragment screening molecules at two substrate binding sites.

Publications

Structural characterization of β-ketoacyl ACP synthase I bound to platencin and fragment screening molecules at two substrate binding sites.

Similar Datasets

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