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1.  Genome Mining for Ribosomally Synthesized Natural Products 
In recent years, the number of known peptide natural products that are synthesized via the ribosomal pathway has rapidly grown. Taking advantage of sequence homology among genes encoding precursor peptides or biosynthetic proteins, in silico mining of genomes combined with molecular biology approaches has guided the discovery of a large number of new ribosomal natural products, including lantipeptides, cyanobactins, linear thiazole/oxazole-containing peptides, microviridins, lasso peptides, amatoxins, cyclotides, and conopeptides. In this review, we describe the strategies used for the identification of these ribosomally-synthesized and posttranslationally modified peptides (RiPPs) and the structures of newly identified compounds. The increasing number of chemical entities and their remarkable structural and functional diversity may lead to novel pharmaceutical applications.
doi:10.1016/j.cbpa.2010.10.027
PMCID: PMC3090663  PMID: 21095156
2.  Substrate Control in Stereoselective Lanthionine Biosynthesis 
Nature chemistry  2014;7(1):57-64.
Enzymes are typically highly stereoselective catalysts that enforce a reactive conformation on their native substrates. We report here a rare example where the substrate controls the stereoselectivity of an enzyme-catalyzed Michael-type addition during the biosynthesis of lanthipeptides. These natural products contain thioether crosslinks formed by cysteine attack on dehydrated Ser and Thr residues. We demonstrate that several lanthionine synthetases catalyze highly selective anti additions in which the substrate (and not the enzyme) determines whether the addition occurs from the Re or Si face. A single point mutation in the peptide substrate completely inverted the stereochemical outcome of the enzymatic modification. Quantum mechanical calculations reproduced the experimentally observed selectivity and suggest that conformational restraints imposed by the amino acid sequence on the transition states determine the face selectivity of the Michael-type cyclization.
doi:10.1038/nchem.2113
PMCID: PMC4270103  PMID: 25515891
3.  Mechanistic Studies on the Substrate-Tolerant Lanthipeptide Synthetase ProcM 
Journal of the American Chemical Society  2014;136(29):10450-10459.
Lanthipeptides are a class of post-translationally modified peptide natural products. They contain lanthionine (Lan) and methyllanthionine (MeLan) residues, which generate cross-links and endow the peptides with various biological activities. The mechanism of a highly substrate-tolerant lanthipeptide synthetase, ProcM, was investigated herein. We report a hybrid ligation strategy to prepare a series of substrate analogues designed to address a number of mechanistic questions regarding catalysis by ProcM. The method utilizes expressed protein ligation to generate a C-terminal thioester of the leader peptide of ProcA, the substrate of ProcM. This thioester was ligated with a cysteine derivative that resulted in an alkyne at the C-terminus of the leader peptide. This alkyne in turn was used to conjugate the leader peptides to a variety of synthetic peptides by copper-catalyzed azide–alkyne cycloaddition. Using deuterium-labeled Ser and Thr in the substrate analogues thus prepared, dehydration by ProcM was established to occur from C-to-N-terminus for two different substrates. Cyclization also occurred with a specific order, which depended on the sequence of the substrate peptides. Furthermore, using orthogonal cysteine side-chain protection in the two semisynthetic peptide substrates, we were able to rule out spontaneous non-enzymatic cyclization events to explain the very high substrate tolerance of ProcM. Finally, the enzyme was capable of exchanging protons at the α-carbon of MeLan, suggesting that ring formation could be reversible. These findings are discussed in the context of the mechanism of the substrate-tolerant ProcM, which may aid future efforts in lanthipeptide engineering.
doi:10.1021/ja504692v
PMCID: PMC4111213  PMID: 24972336
4.  Substrate Specificity of the Lanthipeptide Peptidase ElxP and the Oxidoreductase ElxO 
ACS Chemical Biology  2014;9(8):1718-1725.
The final step in lanthipeptide biosynthesis involves the proteolytic removal of an N-terminal leader peptide. In the class I lanthipeptide epilancin 15X, this step is performed by the subtilisin-like serine peptidase ElxP. Bioinformatic, kinetic, and mass spectrometric analysis revealed that ElxP recognizes the stretch of amino acids DLNPQS located near the proteolytic cleavage site of its substrate, ElxA. When the ElxP recognition motif was inserted into the noncognate lanthipeptide precursor NisA, ElxP was able to proteolytically remove the leader peptide from NisA. Proteolytic removal of the leader peptide by ElxP during the biosynthesis of epilancin 15X exposes an N-terminal dehydroalanine on the core peptide of ElxA that hydrolyzes to a pyruvyl group. The short-chain dehydrogenase ElxO reduces the pyruvyl group to a lactyl moiety in the final step of epilancin 15X maturation. Using synthetic peptides, we also investigated the substrate specificity of ElxO and determined the 1.85 Å resolution X-ray crystal structure of the enzyme.
doi:10.1021/cb5002526
PMCID: PMC4136673  PMID: 24866416
5.  Synergistic binding of the leader and core peptides by the lantibiotic synthetase HalM2 
ACS chemical biology  2015;10(4):970-977.
Lanthipeptides are a class of ribosomally-produced and post-translationally modified peptides (RiPPs) that possess a variety of biological activities, but typically act as antimicrobial agents (lantibiotics). Haloduracin is a lantibiotic that is composed of two post-translationally modified peptides, Halα and Halβ, which are biosynthesized from the precursor peptides HalA1 and HalA2 by their cognate lanthipeptide synthetases, HalM1 and HalM2, respectively. Co-expression studies of HalM1 and HalM2 with chimeric peptides consisting of the leader peptide of HalA1 and the core peptide of HalA2 (or vice versa) showed that the synthetases require both the cognate leader and core peptides for efficient processing. Investigation of the affinity in vitro showed that binding of the N-terminal leader peptide by HalM2 increases its affinity for the C-terminal core peptide. Thus, the two segments of the precursor peptide HalA2 synergistically bind to HalM2.
doi:10.1021/cb5009876
PMCID: PMC4414810  PMID: 25619528
6.  Conjugation to Albumin-Binding Molecule Tags as a Strategy to Improve Both Efficacy and Pharmacokinetic Properties of the Complement Inhibitor Compstatin 
ChemMedChem  2014;9(10):2223-2226.
The compstatin family of complement inhibitors has shown promise in various immuno-inflammatory disorders. Although recent analogues show beneficial pharmacokinetics, further extension of the plasma half-life is expected to benefit systemic application of these peptidic inhibitors. We therefore synthesized conjugates of compstatin analogues and albumin-binding molecules (ABM) to increase circulatory residence. Equilibrium dialysis in complement-depleted serum showed a marked increase in plasma protein binding from <8% to >99% for a resulting chimera (ABM2-Cp20). Further analysis confirmed interaction with albumin from different species, primarily via site II. Importantly, ABM2-Cp20 bound 20-fold stronger to its target protein C3b (KD=150 pm) than the parent peptide. Kinetic and in silico analysis suggested that ABM2 occupies a secondary site on C3b and improves the dissociation rate via additional contacts. Addition of an ABM modifier thereby not only improved plasma protein binding but also produced the most potent compstatin analogue to date with potential implications for the treatment of systemic complement-related diseases.
doi:10.1002/cmdc.201402212
PMCID: PMC4177305  PMID: 25056114
albumin binding; complement inhibitor; compstatin; conjugation; peptide drugs
7.  Lanthionine synthetase C–like protein 2 (LanCL2) is a novel regulator of Akt 
Molecular Biology of the Cell  2014;25(24):3954-3961.
Lanthionine synthetase C-like 2 (LanCL2) is a novel regulator of Akt, promoting maximum Akt activation and cell survival in liver cells. LanCL2 regulates Akt activation by directly facilitating mTORC2 phosphorylation of Akt.
The serine/threonine protein kinase Akt controls a wide range of biochemical and cellular processes under the modulation of a variety of regulators. In this study, we identify the lanthionine synthetase C–like 2 (LanCL2) protein as a positive regulator of Akt activation in human liver cells. LanCL2 knockdown dampens serum- and insulin-stimulated Akt phosphorylation, whereas LanCL2 overexpression enhances these processes. Neither insulin receptor phosphorylation nor the interaction between insulin receptor substrate and phosphatidylinositide 3-kinase (PI3K) is affected by LanCL2 knockdown. LanCL2 also does not function through PP2A, a phosphatase of Akt. Instead, LanCL2 directly interacts with Akt, with a preference for inactive Akt. Moreover, we show that LanCL2 also binds to the Akt kinase mTORC2, but not phosphoinositide-dependent kinase 1. Whereas LanCL2 is not required for the Akt-mTORC2 interaction, recombinant LanCL2 enhances Akt phosphorylation by target of rapamycin complex 2 (mTORC2) in vitro. Finally, consistent with a function of Akt in regulating cell survival, LanCL2 knockdown increases the rate of apoptosis, which is reversed by the expression of a constitutively active Akt. Taken together, our findings reveal LanCL2 as a novel regulator of Akt and suggest that LanCL2 facilitates optimal phosphorylation of Akt by mTORC2 via direct physical interactions with both the kinase and the substrate.
doi:10.1091/mbc.E14-01-0004
PMCID: PMC4244203  PMID: 25273559
8.  Structural and Mechanistic Insights into C-P Bond Hydrolysis by Phosphonoacetate Hydrolase 
Chemistry & biology  2011;18(10):1230-1240.
SUMMARY
Bacteria have evolved pathways to metabolize phosphonates as a nutrient source for phosphorus. In Sinorhizobium meliloti 1021, 2-aminoethylphosphonate is catabolized to phosphonoacetate, which is converted to acetate and inorganic phosphate by phosphonoacetate hydrolase (PhnA). Here we present detailed biochemical and structural characterization of PhnA that provides insights into the mechanism of C-P bond cleavage. The 1.35 Å resolution crystal structure reveals a catalytic core similar to those of alkaline phosphatases and nucleotide pyrophosphatases, but with notable differences such as a longer metal-metal distance. Detailed structure-guided analysis of active site residues and four additional co-crystal structures with phosphonoacetate substrate, acetate, phosphonoformate inhibitor, and a covalently-bound transition state mimic, provide insight into active site features that may facilitate cleavage of the C-P bond. These studies expand upon the array of reactions that can be catalyzed by enzymes of the alkaline phosphatase superfamily.
doi:10.1016/j.chembiol.2011.07.019
PMCID: PMC4321816  PMID: 22035792
9.  Crystal Structures of Phosphite Dehydrogenase Provide Insights into Nicotinamide Cofactor Regeneration 
Biochemistry  2012;51(21):4263-4270.
The enzyme phosphite dehydrogenase (PTDH) catalyzes the NAD+-dependent conversion of phosphite to phosphate and represents the first biological catalyst that has been characterized to carry out the enzymatic oxidation of phosphorus. Despite over a decade’s worth of investigation into both the mechanism of its unusual reaction, as well as its utility in cofactor regeneration, there has been a lack of any structural data on PTDH. Here we present the co-crystal structure of an engineered thermostable variant of PTDH bound to NAD+ (1.7 Å resolution), as well as four other co-crystal structures of thermostable PTDH and its variants with different ligands (all between 1.85 – 2.3 Å resolution). These structures provide a molecular framework for understanding prior mutational analysis, and point to additional residues, located in the active site, that may contribute to the enzymatic activity of this highly unusual catalyst.
doi:10.1021/bi2016926
PMCID: PMC4316821  PMID: 22564171
10.  Structure and function of phosphonoacetaldehyde dehydrogenase: the missing link in phosphonoacetate formation 
Chemistry & biology  2013;21(1):125-135.
Summary
Phosphonates (C-PO32−) have application as antibiotics, herbicides and detergents. In some environments, these molecules represent the predominant source for phosphorus, and several microbes have evolved dedicated enzymatic machineries for phosphonate degradation. For example, most common naturally occurring phosphonates can be catabolized to either phosphonoacetaldehyde or phosphonoacetate, which can then be hydrolyzed to generate inorganic phosphate and acetaldehyde or acetate, respectively. The phosphonoacetaldehyde oxidase gene (phnY) links these two hydrolytic processes and provides a previously unknown catabolic mechanism for phosphonoacetate production in the microbial metabolome. Here, we present biochemical characterization of PhnY and high-resolution crystal structures of the apo state, as well as complexes with substrate, cofactor and product. Kinetic analysis of active site mutants demonstrates how a highly conserved aldehyde dehydrogenase active site has been modified in nature to generate activity with a phosphonate substrate.
doi:10.1016/j.chembiol.2013.11.006
PMCID: PMC4313731  PMID: 24361046
11.  Unusual transformations in the biosynthesis of the antibiotic phosphinothricin tripeptide 
Nature chemical biology  2007;3(8):480-485.
Phosphinothricin-tripeptide (PTT, phosphinothricyl-alanyl-alanine) is a natural product antibiotic and potent herbicide that is produced by Streptomyces hygroscopicus ATCC 217051 and Streptomyces viridochromogenes DSM 407362. PTT has attracted widespread interest due to its commercial applications and unique phosphinic acid functional group. Despite intensive study since its discovery in 1972 (see3 for a comprehensive review), a number of steps early in the PTT biosynthetic pathway remain uncharacterized. Here we report a series of interdisciplinary experiments involving the construction of defined S. viridochromogenes mutants, chemical characterization of accumulated intermediates, and in vitro assay of selected enzymes to examine these critical steps in PTT biosynthesis. Our results indicate that early PTT biosynthesis involves a series of heretofore undescribed catalyses, including a highly unusual reaction for carbon bond cleavage. In sum, we define a more complex pathway for early PTT biosynthesis that includes biochemically unprecedented and chemically interesting steps.
doi:10.1038/nchembio.2007.9
PMCID: PMC4313788  PMID: 17632514
Streptomyces viridochromogenes; phosphinothricin; biosynthesis; bialaphos; phosphonate metabolism
12.  The glycosyltransferase involved in thurandacin biosynthesis catalyzes both O- and S-glycosylation 
The S-glycosyltransferase SunS is a recently discovered enzyme that selectively catalyzes the conjugation of carbohydrates to the cysteine thiol of proteins. This study reports the discovery of a second S-glycosyltransferase, ThuS, and shows that ThuS catalyzes both S-glycosylation of the thiol of cysteine and O-glycosylation of the hydroxyl group of serine in peptide substrates. ThuS-catalyzed S-glycosylation is more efficient than O-glycosylation and the enzyme demonstrates high tolerance with respect to both nucleotide sugars and peptide substrates. The biosynthesis of the putative products of the thuS gene cluster were reconstituted in vitro and the resulting S-glycosylated peptides thurandacin A and thurandacin B exhibit highly selective antimicrobial activity towards Bacillus thuringiensis.
doi:10.1021/ja411159k
PMCID: PMC3913795  PMID: 24325644
13.  NMR Structure of the S-Linked Glycopeptide Sublancin 168 
ACS Chemical Biology  2014;9(3):796-801.
Sublancin 168 is a member of a small group of glycosylated antimicrobial peptides known as glycocins. The solution structure of sublancin 168, a 37-amino-acid peptide produced by Bacillus subtilis 168, has been solved by nuclear magnetic resonance (NMR) spectroscopy. Sublancin comprises two α-helices and a well-defined interhelical loop. The two helices span residues 6–16 and 26–35, and the loop region encompasses residues 17–25. The 9-amino-acid loop region contains a β-S-linked glucose moiety attached to Cys22. Hydrophobic interactions as well as hydrogen bonding are responsible for the well-structured loop region. The three-dimensional structure provides an explanation for the previously reported extraordinary high stability of sublancin 168.
doi:10.1021/cb4008106
PMCID: PMC3985867  PMID: 24405370
14.  Mode of Action and Structure-Activity Relationship Studies of Geobacillin I 
The Journal of antibiotics  2013;67(1):133-136.
doi:10.1038/ja.2013.112
PMCID: PMC4004768  PMID: 24169799
lanthionine; lantibiotics/membrane disruption; mode of action; nisin; lipid II
15.  Stereochemistry of Hydride Transfer by Group III Alcohol Dehydrogenases Involved in Phosphonate Biosynthesis 
MedChemComm  2012;3(8):967-970.
doi:10.1039/C2MD20009K
PMCID: PMC4231301  PMID: 25400901
biosynthesis; phosphonate; fosfomycin; stereochemistry; alcohol dehydrogenase
16.  Phosphonate Biosynthesis and Catabolism: A Treasure Trove of Unusual Enzymology 
Natural product biosynthesis has proven a fertile ground for the discovery of novel chemistry. Herein we review the progress made in elucidating the biosynthetic pathways of phosphonate and phosphinate natural products such as the antibacterial compounds dehydrophos and fosfomycin, the herbicidal phosphinothricin-containing peptides, and the antimalarial compound FR-900098. In each case, investigation of the pathway has yielded unusual, and often unprecedented, biochemistry. Likewise, recent investigations have uncovered novel ways to cleave the C-P bond to yield phosphate under phosphorus starvation conditions. These include the discovery of novel oxidative cleavage of the C-P bond catalyzed by PhnY and PhnZ as well as phosphonohydrolases that liberate phosphate from phosphonoacetate. Perhaps the crown jewel of phosphonate catabolism has been the recent resolution of the longstanding problem of the C-P lyase responsible for reductively cleaving the C-P bond of a number of different phosphonates to release phosphate. Taken together, the strides made on both metabolic and catabolic fronts illustrate an array of fascinating biochemistry.
doi:10.1016/j.cbpa.2013.06.018
PMCID: PMC3764496  PMID: 23870698
17.  Characterization and Application of the Fe(II) and α-Ketoglutarate Dependent Hydroxylase FrbJ 
The Fe(II) and α-ketoglutarate-dependent hydroxylase FrbJ was previously demonstrated to utilize FR-900098 synthesizing a second phosphonate FR-33289. Here we assessed its ability to hydroxylate other possible substrates, generating a library of potential antimalarial compounds. Through a series of bioassays and in vitro experiments, we identified two new antimalarials.
doi:10.1039/c1cc13597j
PMCID: PMC4091617  PMID: 21829824
18.  Ribosomally Synthesized and Post-translationally Modified Peptide Natural Products: New Insights Into the Role of Leader and Core Peptides During Biosynthesis 
Chemistry (Weinheim an der Bergstrasse, Germany)  2013;19(24):10.1002/chem.201300401.
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products with a high degree of structural diversity and a wide variety of bioactivities. Understanding the biosynthetic machinery of these RiPPs will benefit the discovery and development of new molecules with potential pharmaceutical applications. In this review, we discuss the features of the biosynthetic pathways to different RiPP classes, and propose mechanisms regarding recognition of the precursor peptide by the posttranslational modification enzymes. We propose that the leader peptides function as allosteric regulators that bind the active form of the biosynthetic enzymes in a conformational selection process. We also speculate how enzymes that generate polycyclic products of defined topologies may have been selected for during evolution.
doi:10.1002/chem.201300401
PMCID: PMC3838977  PMID: 23666908
natural products; peptides; biosynthesis
19.  Discovery of the antibiotic phosacetamycin via a new mass spectrometry-based method for phosphonic acid detection 
ACS chemical biology  2013;8(5):908-913.
Naturally occurring phosphonates such as phosphinothricin (Glufosinate, a commercially used herbicide) and fosfomycin (Monurol, a clinically used antibiotic) have proved to be potent and useful biocides. Yet this class of natural products is still an under explored family of secondary metabolites. Discovery of the biosynthetic pathways responsible for the production of these compounds has been simplified by using gene based screening approaches, but detection and identification of the natural products the genes produce has been hampered by a lack of high-throughput methods for screening potential producers under various culture conditions. Here we present an efficient mass-spectrometric method for the selective detection of natural products containing phosphonate and phosphinate functional groups. We have used this method to identify a new phosphonate metabolite, phosacetamycin, whose structure, biological activity, and biosynthetic gene cluster are reported.
doi:10.1021/cb400102t
PMCID: PMC3657337  PMID: 23474169
Secondary metabolism; natural products; phosphonates; antibiotics; mass spectrometry
20.  Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature 
Natural product reports  2013;30(1):108-160.
This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.
doi:10.1039/c2np20085f
PMCID: PMC3954855  PMID: 23165928
21.  Chemical Rescue and Inhibition Studies to Determine the Role of Arg301 in Phosphite Dehydrogenase 
PLoS ONE  2014;9(1):e87134.
Phosphite dehydrogenase (PTDH) catalyzes the NAD+-dependent oxidation of phosphite to phosphate. This reaction requires the deprotonation of a water nucleophile for attack on phosphite. A crystal structure was recently solved that identified Arg301 as a potential base given its proximity and orientation to the substrates and a water molecule within the active site. Mutants of this residue showed its importance for efficient catalysis, with about a 100-fold loss in kcat and substantially increased Km,phosphite for the Ala mutant (R301A). The 2.35 Å resolution crystal structure of the R301A mutant with NAD+ bound shows that removal of the guanidine group renders the active site solvent exposed, suggesting the possibility of chemical rescue of activity. We show that the catalytic activity of this mutant is restored to near wild-type levels by the addition of exogenous guanidinium analogues; Brønsted analysis of the rates of chemical rescue suggests that protonation of the rescue reagent is complete in the transition state of the rate-limiting step. Kinetic isotope effects on the reaction in the presence of rescue agents show that hydride transfer remains at least partially rate-limiting, and inhibition experiments show that Ki of sulfite with R301A is ∼400-fold increased compared to the parent enzyme, similar to the increase in Km for phosphite in this mutant. The results of our experiments indicate that Arg301 plays an important role in phosphite binding as well as catalysis, but that it is not likely to act as an active site base.
doi:10.1371/journal.pone.0087134
PMCID: PMC3909101  PMID: 24498026
22.  A General Method for Fluorescent Labeling of the N-termini of Lanthipeptides and Its Application to Visualize their Cellular Localization 
Journal of the American Chemical Society  2013;135(28):10362-10371.
Labeling of natural products with biophysical probes has greatly contributed to investigations of their modes of action and has provided tools for visualization of their targets. A general challenge is the availability of a suitable functional group for chemoselective modification. We demonstrate here that an N-terminal ketone is readily introduced into various lanthipeptides by the generation of a cryptic N-terminal dehydro amino acid by the cognate biosynthetic enzymes. Spontaneous hydrolysis of the N-terminal enamines results in α-ketoamides that site-specifically react with an aminooxy-derivatized alkyne or fluorophore. The methodology was successfully applied to prochlorosins 1.7 and 2.8, as well as the lantibiotics lacticin 481, haloduracin α, and haloduracin β. The fluorescently-modified lantibiotics were added to bacteria, and their cellular localization was visualized by confocal fluorescence microscopy. Lacticin 481 and haloduracin α localized predominantly at sites of new and old cell division as well as in punctate patterns along the long axis of rod shaped bacilli, similar to the localization of lipid II. On the other hand, haloduracin β was localized non-specifically in the absence of haloduracin α, but formed specific patterns when co-administered with haloduracin α. Using two-color labeling, colocalization of both components of the two-component lantibiotic haloduracin was demonstrated. These data with living cells supports a model in which the α component recognizes lipid II and then recruits the β-component.
doi:10.1021/ja4010706
PMCID: PMC3775354  PMID: 23789944
23.  Heterologous Production of the Lantibiotic Ala(0)Actagardine in Escherichia coli† 
We report the heterologous production of Ala(0)actagardine in E. coli by co-expression of the substrate peptide GarA and its modification enzymes GarM and GarO. The activity of GarO, a luciferase-like monooxygenase that introduces the unique sulfoxide group of actagardine, was also investigated in vitro.
doi:10.1039/c2cc36336d
PMCID: PMC3485686  PMID: 23034674
24.  Chemical Synthesis of the Lantibiotic Lacticin 481 Reveals the Importance of Lanthionine Stereochemistry 
Lantibiotics are a family of antibacterial peptide natural products characterized by the posttranslational installation of the thioether-containing amino acids lanthionine and methyllanthionine. Until recently, only a single stereochemical configuration for each of these crosslinks was known in Nature. The discovery of lantibiotics with alternative lanthionine and methyllanthionine stereochemistry has prompted an investigation of its importance to biological activity. Here, solid-supported chemical synthesis enabled the total synthesis of the lantibiotic lacticin 481 and analogues containing crosslinks with non-native stereochemical configuration. Biological evaluation revealed that these alterations abolished antibacterial activity in all analogues, revealing the critical importance of the enzymatically-installed stereochemistry for the biological activity of lacticin 481.
doi:10.1021/ja4014024
PMCID: PMC3736828  PMID: 23621626
25.  Follow the leader: The use of leader peptides to guide natural product biosynthesis 
Nature chemical biology  2010;6(1):9-18.
The avalanche of genomic information in the past decade has revealed that natural product biosynthesis using the ribosomal machinery is much more widespread than originally anticipated. Nearly all of these compounds are crafted through posttranslational modifications of a larger precursor peptide that often contains the marching orders for the biosynthetic enzymes. We review here the available information for how the peptide sequences in the precursors govern the posttranslational tailoring processes for several classes of natural products. In addition, we highlight the great potential these leader peptide directed biosynthetic systems offer for engineering conformationally restrained and pharmacophore-rich products with structural diversity that greatly expands the proteinogenic repertoire.
doi:10.1038/nchembio.286
PMCID: PMC3799897  PMID: 20016494

Results 1-25 (97)