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. 2009 Jun 9;19(11):R437-41.
doi: 10.1016/j.cub.2009.04.001.

The natural history of antibiotics

Jon Clardy  1 , Michael A Fischbach, Cameron R Currie
Affiliations

The natural history of antibiotics

Jon Clardy et al. Curr Biol. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Biosynthetic pathways for the antibiotics penicillin, tetracycline, streptomycin, and thiocillin
(A) Penicillin. The modular portion of the penicillin pathway is shown; each circle or oval represents a separate protein domain, and the domains are organized into three modules (red, blue, and green). These modules comprise a single ten-domain protein, isopenicillin N synthetase. The logic of penicillin synthesis is similar to that of protein synthesis by the ribosome: each newly-arrived building block gets linked to its module and then bonded to the nascent peptide chain attached to the upstream module. Bond formation translocates the chain to the downstream module. 1) α-aminoadipate, a nonproteinogenic amino acid, is selected and activated by the blue module. 2) The activated form of α-aminoadipate is loaded onto the carrier domain of the blue module. 3) Cysteine is selected and activated by the red module. 4) Cysteine is linked to the red module and then coupled to the α-aminoadipate linked to the blue module, forming a peptide bond and translocating the chain to the red module. 5) Valine is selected and activated by the green module. 6) Valine is linked to the green module and then coupled to the α-aminoadipate-cysteine dipeptide linked to the red module, forming a new peptide bond and translocating the chain to the green module. 7) The chain is released from the green module. Post-assembly modifications convert the penicillin precursor into penicillin N. (B) Tetracyline. The enzymes in the early part of the tetracycline pathway are distant homologs of fatty acid synthase (FAS); like FAS, they iteratively couple C2 building blocks (colored red, green, and blue) to synthesize a long chain. By omitting the beta-carbon reduction and subsequent steps, the tetracycline pathway produces a polyketone chain rather than a saturated lipid chain. Three enzymes control the cyclization of the polyketone chain into a precursor with four fused rings, and post-assembly modifications convert the precursor into tetracycline. (C) Streptomycin. Three different sets of enzymes convert the primary metabolite glucose-6-phosphate into the three building blocks of streptomycin, colored blue, red, and green. Two coupling enzymes related to sugar-coupling enzymes from primary metabolic pathways link these building blocks, and post-assembly modifications turn the nascent trisaccharide into streptomycin. (D) Thiocillin. The last fourteen amino acids of a 52-residue peptide undergo thirteen post-translational modifications – including cleavage of the 38-residue ‘leader peptide’ – to become thiocillin. Only a single residue – a threonine (shown in black in the lower left-hand portion of the molecule) – remains unmodified.
Figure 2
Figure 2. Exploring the natural history of antibiotics by focusing on ancient agriculture in ants
Fungus-growing ants, including the conspicuous leaf-cutters (A), cultivate fungus for food (B). The ants engage in another mutualism with actinomycetes, which can completely cover the exoskeleton of workers ((C); whitish substance on Acromyrmex sp.), or occur within specialized crypts, on the ventral surface of the ants ((D); propleura in Cyphomyrmex longiscapus) and can even cover the most of the surface of workers ((E); white dots on exoskeleton of C. longiscapus represent openings to crypts). The symbiotic actinomycete produce antibiotics that help protect the garden from specialized parasites in the genus Escovopsis ((F); bioassay with bacterium in middle and parasite Escovopsis on the left side). (Photocredits: A,B, Alex Wild; C Ainslie Little)
See this image and copyright information in PMC

References

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