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The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for

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  • Authors: Wanisa Salaemae1, Grant W. Booker2, Steven W. Polyak4
  • Editors: Indira T. Kudva6, Bryan H. Bellaire7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Molecular and Cellular Biology, School of Biological Science, The University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia; 2: Department of Molecular and Cellular Biology, School of Biological Science, The University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia; 3: Center for Molecular Pathology, University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia; 4: Department of Molecular and Cellular Biology, School of Biological Science, The University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia; 5: Center for Molecular Pathology, University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia; 6: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 7: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA
  • Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
  • Received 16 February 2015 Accepted 16 November 2015 Published 08 April 2016
  • Steven W. Polyak, steven.polyak@adelaide.edu.au
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  • Abstract:

    Biotin is an essential cofactor for enzymes present in key metabolic pathways such as fatty acid biosynthesis, replenishment of the tricarboxylic acid cycle, and amino acid metabolism. Biotin is synthesized in microorganisms, plants, and fungi, but this metabolic activity is absent in mammals, making biotin biosynthesis an attractive target for antibiotic discovery. In particular, biotin biosynthesis plays important metabolic roles as the sole source of biotin in all stages of the life cycle due to the lack of a transporter for scavenging exogenous biotin. Biotin is intimately associated with lipid synthesis where the products form key components of the mycobacterial cell membrane that are critical for bacterial survival and pathogenesis. In this review we discuss the central role of biotin in bacterial physiology and highlight studies that demonstrate the importance of its biosynthesis for virulence. The structural biology of the known biotin synthetic enzymes is described alongside studies using structure-guided design, phenotypic screening, and fragment-based approaches to drug discovery as routes to new antituberculosis agents.

  • Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for . Microbiol Spectrum 4(2):VMBF-0008-2015. doi:10.1128/microbiolspec.VMBF-0008-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0008-2015
2016-04-08
2017-09-22

Abstract:

Biotin is an essential cofactor for enzymes present in key metabolic pathways such as fatty acid biosynthesis, replenishment of the tricarboxylic acid cycle, and amino acid metabolism. Biotin is synthesized in microorganisms, plants, and fungi, but this metabolic activity is absent in mammals, making biotin biosynthesis an attractive target for antibiotic discovery. In particular, biotin biosynthesis plays important metabolic roles as the sole source of biotin in all stages of the life cycle due to the lack of a transporter for scavenging exogenous biotin. Biotin is intimately associated with lipid synthesis where the products form key components of the mycobacterial cell membrane that are critical for bacterial survival and pathogenesis. In this review we discuss the central role of biotin in bacterial physiology and highlight studies that demonstrate the importance of its biosynthesis for virulence. The structural biology of the known biotin synthetic enzymes is described alongside studies using structure-guided design, phenotypic screening, and fragment-based approaches to drug discovery as routes to new antituberculosis agents.

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Figures

Image of FIGURE 1
FIGURE 1

Biotin biosynthetic pathway. The proposed synthesis of biotin precursors and the conserved metabolic pathway (dashed box) are shown. The atoms modified in each step are highlighted in bold text. Abbreviations: ACP, acyl carrier protein; AaaS, acyl-ACP synthetase; AMTB, -adenosyl-2-oxo-4-methylthiobutyric acid; DOA, 5′-deoxyadenosine; FAS, fatty acid synthesis; SAM, -adenosyl--methionine; SAH, S-adenosylhomocysteine. Figure adapted from Lin and Cronan ( 85 ).

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Image of FIGURE 2
FIGURE 2

Structures of biotin biosynthetic enzymes. The crystal structure of BioH S82A from is shown (gray ribbon) in complex with pimeloyl-ACP methyl ester (in purple) and an acyl carrier protein partner (in blue) (PDB 4ETW). Residues in the catalytic triad, namely, Ser82, Asp207, and His235 (in green), are located at the interface between the two domains. One subunit of the KAPAS homodimer is shown in complex with KAPA-PLP aldimine intermediate (shown in pink connected to blue, respectively) (PDB 1DJ9). The Mg ion is shown in green. The homodimer of DAPAS formed by two subunits, chain A (in gray) and chain B (in green). The enzyme was crystallized in complex with PLP cofactor (in blue) and KAPA substrate (in pink) (PDB 4CXQ). The homodimer of DTBS is formed by two subunits: chain A (in gray) and chain B (in green). The structure of the mycobacterial enzyme has been reported in complex with DAPA carbamate (PDB 3FMF) or CTP (PDB 4WOP). Two active sites are located at the interface between the subunits where each active site contains two adjacent binding pockets of DAPA carbamate (in red) and CTP (in yellow). The crystal structure of BS was determined in complex with SAM (in orange) and DTB (in blue) (PDB 1R30). Each subunit, chain A (in gray) and chain B (in green), of the homodimer folds as a triosephosphate isomerase type (α/β) barrel with extensions on the N- and C-terminal ends. BS contains one [4Fe-4S] and one [2Fe-2S] per monomer as highlighted in yellow.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Image of FIGURE 3
FIGURE 3

Chemical structures of BioC substrate and inhibitors. -adenosyl -methionine substrate. -adenosylhomocysteine product of BioC reaction. Sinefungin.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Image of FIGURE 4
FIGURE 4

Chemical structures of KAPAS substrate, reaction intermediate, and inhibitors. -alanine. -trifluroalanine. -alanine. -KAPA. The aldimine reaction intermediate. (±)-8-amino-7-oxo-8-phosphonononaoic acid. 4-carboxybutyl (1-amino-1-carboxyethyl) phosphate. 2-amino-3-hydroxy-2-methylnonadioic acid. Abbreviation: Pyr, pyrimidine ring of the PLP cofactor.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Image of FIGURE 5
FIGURE 5

Chemical structures of DAPAS inhibitors. Cis-amiclenomycin. Trans-amiclenomycin. 8-amino-7-oxooctanoic acid. MAC13772. Aryl hydrazine.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Image of FIGURE 6
FIGURE 6

Chemical structures of DTBS inhibitor. A phosphate-based mimic of DAPA carbamate. 6-hydroxypyrimidin-4(3H)-one (also known as 6-HP4).

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Image of FIGURE 7
FIGURE 7

Chemical structures of BS inhibitors. Actithiazic acid. α-methyldethiobiotin. α-methylbiotin.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015
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Tables

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TABLE 1

Structural biology of biotin biosynthetic enzymes and crystallographic data for the biotin biosynthetic enzymes

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0008-2015

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