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Chapter 8 : Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate

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Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, Page 1 of 2

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Abstract:

Replication of DNA is required in every cell division that occurs in organisms ranging from prokaryotes to eukaryotes. DNA molecules differ from RNA molecules compositionally in two major respects. The most pervasive change is the use of 2′-deoxyribose in place of ribose in the nucleoside triphosphate building blocks, a change in the DNA scaffold that makes the molecule much more stable than RNA to hydrolytic decomposition at basic pH values and thus more optimal for long-term storage of information. Generally, the interconversion of all four ribonucleotides (for RNA) to deoxyribonucleotides (for DNA) is mediated at the level of nucleoside diphosphates ( Fig. 8.1a ) by ribonucleotide reductase (Nordlund and Reichard, 2006).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Figures

Image of Figure 8.0
Figure 8.0

Antifolate combinations are broad-spectrum front-line therapies for treating bacterial infections. Co-trimoxazole is a fixed-dose 5:1 ratio of sulfamethoxazole and trimethoprim.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.1
Figure 8.1

(a, b) Reaction catalyzed by ribonucleotide reductase occurs at the level of nucleoside diphosphates for all four bases. (c) Conversion of dUMP to 5-Me-dUMP = dTMP by thymidylate synthase as the THF scaffold is oxidized to DHF.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.2
Figure 8.2

Three antibiotic inhibitors of the folate pathway.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.3
Figure 8.3

(a) Thymidylate synthase catalysis involves a ternary adduct between an enzyme active-site cysteine, dUMP, and 5,10-tetrahydrofolate. Formation of the C-methyl group in the dTMP product is formulated as a hydride transfer from C of the folate ring. (b) Dihydrofolate reductase converts the 7,8-dihydrofolate back to 5,6,7,8-tetrahydrofolate by hydride transfer from NADPH to C of dihydrofolate. (c) Serine delivers carbon 3 as formaldehyde to form 5,10-methylenetetrahydrofolate by the action of serine transhydroxymethylase and its cofactor pyridoxyl phosphate (PLP).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.4
Figure 8.4

A three-enzyme cycle (serine transhydroxymethylase, thymidylate synthase, and dihydrofolate reductase) shuttles C of serine to become the 5-methyl group of dTMP for DNA synthesis at the expense of one NADPH oxidized.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.5
Figure 8.5

(a) Dihydropteroate synthase converts the 6-hydroxymethylpterin diphosphate to dihydropteroate by attack of the amine of PABA on the alcoholic diphosphate with C-O bond cleavage and release of PP, and subsequent glutamyl transfer yields dihydrofolate monoglutamate. Subsequent glutamyl transfers generate anionic folate oligoglutamates. The dihydro forms can be reduced to tetrahydro forms. (b) Sulfanilamide can function as a substrate for dihydropteroate synthase, but the product cannot be glutamylated to yield folates.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.6
Figure 8.6

Dihydrofolate synthetase bound to ADP (red) and dihydropteroate acyl phosphate (blue) (PDB file 1W78) (Mathieu et al., 2005).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.7
Figure 8.7

Crystal structures of dihydropteroate synthase bound to (a) -aminobenzoic acid and 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (PDB 3TYB), (b) inhibitor sulfamethoxazole and 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (PDB 3TZF), and (c) dihydropterin-sulfathiazole adduct (PDB 3TYE) (Yun et al., 2012).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.8
Figure 8.8

(a) PABA synthase converts chorismate to PABA in a two-step mechanism. (b) Abyssomicin and its atropisomer are potent inhibitors of PABA synthase. (c) Covalent capture of an active-site Cys by atrop-abyssomicin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.9
Figure 8.9

(a) Variations of clinically used sulfa antibiotics, including the combination of trimethoprim and sulfamethoxazole (b). (c) Iclaprim is a new clinical candidate DHFR inhibitor.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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Image of Figure 8.10
Figure 8.10

Crystal structures of dihydrofolate reductase with NADP cofactor bound to (a) natural substrate dihydrofolate (PDB 1RF7) (Sawaya et al., 1997), (b) inhibitor methotrexate (PDB 3DAU) (Bennett et al., 2009), and (c) inhibitor trimethoprim (PDB 3FRE) (Oefner et al., 2009).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate, p 164-176. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch8
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