scholarly journals Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase

Structure ◽  
2015 ◽  
Vol 23 (12) ◽  
pp. 2213-2223 ◽  
Author(s):  
Dheeraj Khare ◽  
Wendi A. Hale ◽  
Ashootosh Tripathi ◽  
Liangcai Gu ◽  
David H. Sherman ◽  
...  
Keyword(s):  
Acyl Carrier Protein ◽  
Structural Basis ◽  
Carrier Protein

Structural Basis of Acyl-Carrier Protein Interactions in Fatty Acid and Polyketide Biosynthesis

2020 ◽  
pp. 61-122 ◽  
Author(s):  
Jeffrey T. Mindrebo ◽  
Ashay Patel ◽  
Laëtitia E. Misson ◽  
Woojoo E. Kim ◽  
Tony D. Davis ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Interactions ◽  
Acyl Carrier Protein ◽  
Structural Basis ◽  
Carrier Protein ◽  
Polyketide Biosynthesis

Structural basis for the functional and inhibitory mechanisms of β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum

2011 ◽  
Vol 176 (2) ◽  
pp. 238-249 ◽  
Author(s):  
Koustav Maity ◽  
Bharat Somireddy Venkata ◽  
Neha Kapoor ◽  
Namita Surolia ◽  
Avadhesha Surolia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Acyl Carrier Protein ◽  
Structural Basis ◽  
Carrier Protein ◽  
Inhibitory Mechanisms

Structure of β-Ketoacyl-[acyl carrier protein] Reductase fromEscherichia coli:  Negative Cooperativity and Its Structural Basis†,‡

Biochemistry ◽  
2001 ◽  
Vol 40 (43) ◽  
pp. 12772-12781 ◽  
Author(s):  
Allen C. Price ◽  
Yong-Mei Zhang ◽  
Charles O. Rock ◽  
Stephen W. White
Keyword(s):  
Acyl Carrier Protein ◽  
Structural Basis ◽  
Carrier Protein ◽  
Negative Cooperativity ◽  
Fromescherichia Coli

Structure of the prolyl-acyl carrier protein oxidase involved in the biosynthesis of the cyanotoxin anatoxin-a

2013 ◽  
Vol 69 (12) ◽  
pp. 2340-2352 ◽  
Author(s):  
Karine Moncoq ◽  
Leslie Regad ◽  
Stéphane Mann ◽  
Annick Méjean ◽  
Olivier Ploux
Keyword(s):  
Molecular Oxygen ◽  
Acyl Carrier Protein ◽  
Three Dimensional ◽  
Accessible Surface Area ◽  
Polyketide Synthases ◽  
Site Directed Mutagenesis ◽  
Solvent Accessible Surface Area ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Carrier Protein

Anatoxin-a and homoanatoxin-a are two potent cyanobacterial neurotoxins biosynthesized from L-proline by a short pathway involving polyketide synthases. Proline is first loaded onto AnaD, an acyl carrier protein, and prolyl-AnaD is then oxidized to 1-pyrroline-5-carboxyl-AnaD by a flavoprotein, AnaB. Three polyketide synthases then transform this imine into anatoxin-a or homoanatoxin-a. AnaB was crystallized in its holo form and its three-dimensional structure was determined by X-ray diffraction at 2.8 Å resolution. AnaB is a homotetramer and its fold is very similar to that of the acyl-CoA dehydrogenases (ACADs). The active-site base of AnaB, Glu244, superimposed very well with that of human isovaleryl-CoA dehydrogenase, confirming previous site-directed mutagenesis experiments and mechanistic proposals. The substrate-binding site of AnaB is small and is likely to be fitted for the pyrrolidine ring of proline. However, in contrast to ACADs, which use an electron-transport protein, AnaB uses molecular oxygen as the electron acceptor, as in acyl-CoA oxidases. Calculation of the solvent-accessible surface area around the FAD in AnaB and in several homologues showed that it is significantly larger in AnaB than in its homologues. A protonated histidine near the FAD in AnaB is likely to participate in oxygen activation. Furthermore, an array of water molecules detected in the AnaB structure suggests a possible path for molecular oxygen towards FAD. This is consistent with AnaB being an oxidase rather than a dehydrogenase. The structure of AnaB is the first to be described for a prolyl-ACP oxidase and it will contribute to defining the structural basis responsible for oxygen reactivity in flavoenzymes.

scholarly journals Biochemical and Structural Insights Concerning Triclosan Resistance in a Novel YX7K Type Enoyl-Acyl Carrier Protein Reductase from Soil Metagenome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Raees Khan ◽  
Amir Zeb ◽  
Kihyuck Choi ◽  
Gihwan Lee ◽  
Keun Woo Lee ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Fatty Acid Biosynthesis ◽  
Catalytic Domain ◽  
Acyl Carrier Protein ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Carrier Protein ◽  
The Novel ◽  
Triclosan Resistance ◽  
Structural Insights

Abstract Enoyl-acyl carrier protein reductase (ENR) catalyzes the last reduction step in the bacterial type II fatty acid biosynthesis cycle. ENRs include FabI, FabL, FabL2, FabK, and FabV. Previously, we reported a unique triclosan (TCL) resistant ENR homolog that was predominant in obligate intracellular pathogenic bacteria and Apicomplexa. Herein, we report the biochemical and structural basis of TCL resistance in this novel ENR. The purified protein revealed NADH-dependent ENR activity and shared similarity to prototypic FabI. Thus, this metagenome-derived ENR was designated FabI2. Unlike other prototypic bacterial ENRs with the YX6K type catalytic domain, FabI2 possessed a unique YX7K type catalytic domain. Computational modeling followed by site-directed mutagenesis revealed that mild resistance (20 µg/ml of minimum inhibitory concentration) of FabI2 to TCL was confined to the relatively less bulky side chain of A128. Substitution of A128 in FabI2 with bulky valine (V128) elevated TCL resistance. Phylogenetic analysis further suggested that the novel FabI2 and prototypical FabI evolved from a common short-chain dehydrogenase reductase family. To our best knowledge, FabI2 is the only known ENR shared by intracellular pathogenic prokaryotes, intracellular pathogenic lower eukaryotes, and a few higher eukaryotes. This suggests that the ENRs of prokaryotes and eukaryotes diverged from a common ancestral ENR of FabI2.

scholarly journals Biochemical and Structural Basis of Triclosan Resistance in a Novel Enoyl-Acyl Carrier Protein Reductase

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Raees Khan ◽  
Amir Zeb ◽  
Nazish Roy ◽  
Roniya Thapa Magar ◽  
Hyo Jeong Kim ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Carrier Protein ◽  
Content Type ◽  
Triclosan Resistance ◽  
Bacterial Type

ABSTRACTEnoyl-acyl carrier protein reductases (ENR), such as FabI, FabL, FabK, and FabV, catalyze the last reduction step in bacterial type II fatty acid biosynthesis. Previously, we reported metagenome-derived ENR homologs resistant to triclosan (TCL) and highly similar to 7-α hydroxysteroid dehydrogenase (7-AHSDH). These homologs are commonly found inEpsilonproteobacteria, a class that contains several human-pathogenic bacteria, including the generaHelicobacterandCampylobacter. Here we report the biochemical and predicted structural basis of TCL resistance in a novel 7-AHSDH-like ENR. The purified protein exhibited NADPH-dependent ENR activity but no 7-AHSDH activity, despite its high homology with 7-AHSDH (69% to 96%). Because this ENR was similar to FabL (41%), we propose that this metagenome-derived ENR be referred to as FabL2. Homology modeling, molecular docking, and molecular dynamic simulation analyses revealed the presence of an extrapolated six-amino-acid loop specific to FabL2 ENR, which prevented the entry of TCL into the active site of FabL2 and was likely responsible for TCL resistance. Elimination of this extrapolated loop via site-directed mutagenesis resulted in the complete loss of TCL resistance but not enzyme activity. Phylogenetic analysis suggested that FabL, FabL2, and 7-AHSDH diverged from a common short-chain dehydrogenase reductase family. This study is the first to report the role of the extrapolated loop of FabL2-type ENRs in conferring TCL resistance. Thus, the FabL2 ENR represents a new drug target specific for pathogenicEpsilonproteobacteria.

Structural Basis for Substrate Delivery by Acyl Carrier Protein in the Yeast Fatty Acid Synthase

Science ◽  
2007 ◽  
Vol 316 (5822) ◽  
pp. 288-290 ◽  
Author(s):  
M. Leibundgut ◽  
S. Jenni ◽  
C. Frick ◽  
N. Ban
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acyl Carrier Protein ◽  
Structural Basis ◽  
Carrier Protein

Structural Basis for Inhibition of Enoyl-[Acyl Carrier Protein] Reductase (InhA) from Mycobacterium tuberculosis

2020 ◽  
Vol 27 (5) ◽  
pp. 745-759 ◽  
Author(s):  
Maurício Boff de Ávila ◽  
Gabriela Bitencourt-Ferreira ◽  
Walter Filgueira de Azevedo
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Binding Affinity ◽  
Structural Information ◽  
Acyl Carrier Protein ◽  
Computational Prediction ◽  
Multidrug Resistant ◽  
Structural Basis ◽  
Carrier Protein ◽  
Antitubercular Drugs ◽  
Crystallographic Structures

Background:: The enzyme trans-enoyl-[acyl carrier protein] reductase (InhA) is a central protein for the development of antitubercular drugs. This enzyme is the target for the pro-drug isoniazid, which is catalyzed by the enzyme catalase-peroxidase (KatG) to become active. Objective:: Our goal here is to review the studies on InhA, starting with general aspects and focusing on the recent structural studies, with emphasis on the crystallographic structures of complexes involving InhA and inhibitors. Method:: We start with a literature review, and then we describe recent studies on InhA crystallographic structures. We use this structural information to depict protein-ligand interactions. We also analyze the structural basis for inhibition of InhA. Furthermore, we describe the application of computational methods to predict binding affinity based on the crystallographic position of the ligands. Results:: Analysis of the structures in complex with inhibitors revealed the critical residues responsible for the specificity against InhA. Most of the intermolecular interactions involve the hydrophobic residues with two exceptions, the residues Ser 94 and Tyr 158. Examination of the interactions has shown that many of the key residues for inhibitor binding were found in mutations of the InhA gene in the isoniazid-resistant Mycobacterium tuberculosis. Computational prediction of the binding affinity for InhA has indicated a moderate uphill relationship with experimental values. Conclusion:: Analysis of the structures involving InhA inhibitors shows that small modifications on these molecules could modulate their inhibition, which may be used to design novel antitubercular drugs specific for multidrug-resistant strains.

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