Stereochemical fate of (2S,4R)- and (2S,4S)-[4-2H]methionine in nocardicin A biosynthesis

Townsend, Craig A.; Reeve, Anne M.; Salituro, Gino

doi:10.1039/c39880001579

Cited by 8 publications

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“…66A). 615,619,620 Feeding of racemic [2-13 C, 15 N]-pHPG demonstrated that pHPG provides the nitrogen atoms of both the b-lactam and of the oxime in nocardicin A. 621 Employing L-[2-3 H, 1-14 C]-pHPG, it was found that tritium is not incorporated into the 5-position of nocardicin A.…”

Section: Nocardicin Biosynthesismentioning

confidence: 99%

The enzymes of β-lactam biosynthesis

et al. 2013

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The β-lactam antibiotics and related β-lactamase inhibitors are amongst the most important small molecules in clinical use. Most, but not all, β-lactams including penicillins, cephalosporins, and clavulanic acid are produced via fermentation or via modification of fermented intermediates, with important exceptions being the carbapenems and aztreonam. The desire for more efficient routes to existing antibiotics and for access to new and synthetically challenging ones stimulates continued interest in β-lactam biosynthesis. We review knowledge of the pathways leading to β-lactam antibiotics focusing on the mechanisms, structures and biocatalytic applications of the enzymes involved.

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Section: Nocardicin Biosynthesismentioning

confidence: 99%

The enzymes of β-lactam biosynthesis

et al. 2013

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“…2). The stereochemical course of side chain attachment was shown to be inversion through the incorporation of methionine stereospecifically deuterated at C-4 (13). This configurational outcome parallels the stereochemistry of addition of the 3-aminopropyl moiety derived from decarboxylated S-adenosylmethionine (AdoMet) 1 operative in the biosynthesis of the polyamines (14 -16), as well as more conventional methyltransferases (17,18), suggesting a role for AdoMet in nocardicin A biosynthesis in vivo.…”

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confidence: 88%

Purification, Characterization, and Cloning of an S-Adenosylmethionine-dependent 3-Amino-3-carboxypropyltransferase in Nocardicin Biosynthesis

Reeve

Breazeale

Townsend

1998

Journal of Biological Chemistry

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S-Adenosylmethionine:nocardicin 3-amino-3-carboxypropyltransferase catalyzes the biosynthetically rare transfer of the 3-amino-3-carboxypropyl moiety from S-adenosylmethionine to a phenolic site in the ␤-lactam substrates nocardicin E, F, and G, a late step of the biosynthesis of the monocyclic ␤-lactam antibiotic nocardicin A. Whereas a number of conventional methods were ineffective in purifying the transferase, it was successfully obtained by two complementary affinity chromatography steps that took advantage of the two substrate-two product reaction scheme. S-Adenosylhomocysteine-agarose selected enzymes that utilize S-adenosylmethionine, and a second column, nocardicin Aagarose, specifically bound the desired transferase to yield the enzyme as a single band of 38 kDa on a silverstained SDS-polyacrylamide gel. The transferase is active as a monomer and exhibits sequential kinetics. Further kinetic characterization of this protein is described and its role in the biosynthesis of nocardicin A discussed. The gene encoding this transferase was cloned from a sublibrary of Nocardia uniformis DNA. Translation gave a protein of deduced mass 32,386 Da which showed weak homology to small molecule methyltransferases. However, three correctly disposed signature motifs characteristic of these enzymes were observed.

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“…Magnetic susceptibility measurements (SQUID) on microcrystalline samples of 2 (gcfr (300 K) = 2.02 pB, peff (5 K) = 1.73 fiB) indicate that 2 has a larger ground-state orbital contribution than vanadyl (V02+) complexes. 1,11 The IR spectrum of 2 shows a band at 934 cm'1 (t'cr-o)l isotopic labeling12 using 17,1802 resulted in additional absorptions at 917 and 900 cm'1. A crystallographic study shows that 2 adopts a typical piano-stool geometry with very short Cr-07,l2a (1.58 (2) A) and and 2.375 (5) A) distances (Figure 2).…”

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confidence: 99%

“…Careful addition of Br2 to solutions of 2 as well as electrochemical reduction of 2 at -140 mV results in concomitant deoxygenation to give 1. In the thermal conversions (toluene) of 2 to 1,180-labeling studies in conjunction with GC-MS analyses14 indicate that the final oxygen-containing species are polychromatcs (50%), "Cp*OH" (20%), water (10%), (11) Gardner, C. D.; Kendrick, J.; Lambert, P.; Mabbs, F. E.; Hillier, I. H. Inorg. Chem.…”

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confidence: 99%