DANIEL SHER
SCIENCE & TECHNOLOGY
PROMISCUOUS LOCALES Map points
show locations around the world where cyanobacteria with the promiscuous ProcM enzyme have been found. Data are from GOS, a metagenomic database of microbes in ocean surface waters.
A MOST VERSATILE ENZYME Single enzyme catalyzes thioether cyclization of peptides with NEARLY NO SPECIFICITY for amino acid sequence MANY ENZYMES have the flexibility
from a threonine or serine. The second step cyclizes the peptide by linking the dehydroxylated side chain with the thiol group of a cysteine, which could be next door or dozens of residues away. “It’s hard to imagine an active site that can accept this range of substrates,” van der Donk says. The team is currently trying to solve the enzyme’s crystal structure to figure out how it can be so versatile. The structure may help protein engineers figure out what makes ProcM so multitalented and apply the enzyme’s skills to applications as varied as building new antibiotic leads and basic chemical biology.
previously known enzymes operate only on to operate on a pool of similarly shaped a single substrate. “ProcM can cyclize rings THE ENZYME was found in Prochlorococcus, substrates, but rarely is a single enzyme so of drastically different sizes, a ring within which are the smallest and most abundant versatile that it can catalyze a reaction on a ring, overlapping rings, rings that form photosynthetic cells in the oceans and also substrates with radically different shapes. in the direction of a peptide’s carboxyl to have a tiny genome. A “particularly sigNow, in the Prochlorococcus genus of amino termini, and vice versa,” van der nificant” aspect of this study, says Bradley ocean-dwelling cyanobacteria, researchers Donk adds. Moore, who studies marine natural products have discovered and begun to characterize The enzyme’s promiscuity is only riat the University of California, San Diego, is an enzyme that can loop together either valed by “the relaxed specificity of P450 enthat even microbes with small genomes have a serine or a threonine with a cysteine, zymes, which decorate terpenoid products the capacity to synthesize secondary metabregardless of where in plants,” but unlike ProcM, P450 olites that may be crucial for their specialthose amino acids enzymes get help from plant cyclases ized lifestyles. “Previously, the consensus MANY-TRICK PONY are found on peptide to form ring structures, van der Donk was that only microbes with large genomes chains of up to 32 resi- ProcM dehydrates a says. had the luxury of numerous secondary serine or threonine dues long. The final ProcM operates on peptides that metabolic pathways”—such as polyketide residue before making ringed products are are encoded by genes, produced by synthase (PKS) and nonribosomal peptide a thioether bond with a so-called lanthionine- nearby cysteine residue. the ribosome, and have two distinct synthase (NRPS) assembly machinery, containing peptides, a family of natural Peptide Peptide Peptide products used as antibiotics or scaffolds NH Dehydration O NH Cyclization O NH for them. S O OH HS HS “This enzyme’s promiscuity is unO O O HN R HN R HN R believable,” says Wilfred A. van der R = H, CH3 Donk, a chemist at the University of Illinois, Urbana-Champaign, who with Sallie components: First there’s a conserved which require genomes three to four times W. Chisholm of Massachusetts Institute sequence of some 30 amino acids that larger than that of Prochlorococcus—to make of Technology led the team of researchers help ProcM recognize the peptide but specialized products, Moore adds. who studied the ability of the so-called eventually get cleaved off. Then there’s “Prochlorococcus lives in the nutrientProcM enzyme to catalyze formation of an extremely variable selection of 13 to 32 poor oceans, where most free-living 29 structurally unique cyclic peptides residues that ProcM can loop together into bacteria can’t afford to replicate the huge (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/ a lanthionine-containing peptide. genomes for PKS or NRPS machinery, so pnas.0913677107). The cyclization happens in two sequenit makes simple and efficient use of the Although enzymes that catalyze similar tial steps. The first is a dehydration reacribosome and ProcM to produce complex cyclizations had already been found, most tion in which a hydroxyl group is removed metabolites.”—SARAH EVERTS WWW.CEN-ONLINE.ORG
56
MAY 3 1 , 2010
