Chapter 28 : The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for

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The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , Page 1 of 2

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Tuberculosis (TB) is a global pandemic that ranks alongside HIV-AIDS and malaria as the leading cause of death by infectious disease, with the highest incidence rates observed in Southeast Asian, African, and Western Pacific countries ( ). In 1993 the WHO declared TB to be a global health emergency and set the Millennium Development Goal of reducing the prevalence and mortality rates to 50% of those observed in 1990 by the 2015 deadline ( ). Although the rates of new TB cases and mortality have declined over the past decade and are within reach of the 2015 target, the number of TB patients and the prevalence of drug-resistant strains are rising ( ). Multidrug-resistant TB (MDR-TB) must be addressed now as a public health crisis to achieve the ambitious Millennium Development Goal target of complete elimination of TB as a public health concern by 2050 ( ).

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015
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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 ( ).

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. 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.

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. 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.

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015
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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.

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015
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Figure 5

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

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015
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Figure 6

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

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015
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Figure 7

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

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015
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Structural biology of biotin biosynthetic enzymes and crystallographic data for the biotin biosynthetic enzymes

Citation: Salaemae W, Booker G, Polyak S. 2016. The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for , p 797-822. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0008-2015

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