Cobalamin-dependent radical<i>S</i>-adenosyl-<scp>l</scp>-methionine enzymes in natural product biosynthesis

Wang, Susan C.

doi:10.1039/c7np00059f

Cited by 38 publications

(30 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the most attractive features of the Microvirgula system is the ease to introduce C-methylations. Cobalamin-dependent rSAM enzymes that methylate unactivated carbon centers are biochemically intriguing, but technically demanding enzymes with barely utilized synthetic potential 48,49 . With more than 7000 members predicted from sequenced genes, they are involved in the biosynthesis of vitamins and many bioactive compounds including carbapenems, gentamicin, fosfomycin, novobiocins, moenomycins, thiostrepton, and bottromycins [50][51][52][53] .…”

Section: Resultsmentioning

confidence: 99%

Genome mining- and synthetic biology-enabled production of hypermodified peptides

et al. 2019

View full text Add to dashboard Cite

The polytheonamides are among the most complex and biosynthetically distinctive natural products known to date. These potent peptide cytotoxins are derived from a ribosomal precursor processed by 49 mostly non-canonical posttranslational modifications. Since the producer is a "microbial dark matter" bacterium only distantly related to any cultivated organism, >70-step chemical syntheses have been developed to access these unique compounds. Here we mined prokaryotic diversity to establish a synthetic platform based on the new host Microvirgula aerodenitrificans that produces hypermodified peptides within two days. Using this system, we generated the aeronamides, new polytheonamide-type compounds with near-picomolar cytotoxicity. Aeronamides, as well as the polygeonamides produced from deep-rock biosphere DNA, contain the highest numbers of D-amino acids in known biomolecules. With increasing bacterial genomes being sequenced, similar host mining strategies might become feasible to access further elusive natural products from uncultivated life.

show abstract

Section: Resultsmentioning

confidence: 99%

Genome mining- and synthetic biology-enabled production of hypermodified peptides

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Moreover, whether the apparent methyl-transfer reaction plays any role during the oxidative ring contraction catalyzed by OxsB/OxsA or is simply an off-pathway side reaction must await further investigation. Given the atypical activity of OxsB, an in-depth understanding of its chemistry should provide significant insight into the different roles played by Cbl in this class of enzymes, which currently has more than 9000 poorly understood members annotated as B 12 -dependent radical SAM enzymes in the database. , …”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of Oxetanocin-A Includes a B₁₂-Dependent Radical SAM Enzyme That Can Catalyze both Oxidative Ring Contraction and the Demethylation of SAM

et al. 2021

View full text Add to dashboard Cite

Oxetanocin-A is an antitumor, antiviral, and antibacterial nucleoside. It is biosynthesized via the oxidative ring contraction of a purine nucleoside co-opted from primary metabolism. This reaction is catalyzed by a B12-dependent radical S-adenosyl-l-methionine (SAM) enzyme, OxsB, and a phosphohydrolase, OxsA. Previous experiments showed that the product of the OxsB/OxsA-catalyzed reaction is an oxetane aldehyde produced alongside an uncharacterized byproduct. Experiments reported herein reveal that OxsB/OxsA complex formation is crucial for the ring contraction reaction and that reduction of the aldehyde intermediate is catalyzed by a nonspecific dehydrogenase from the general cellular pool. In addition, the byproduct is identified as a 1,3-thiazinane adduct between the aldehyde and l-homocysteine. While homocysteine was never included in the OxsB/OxsA assays, the data suggest that it can be generated from SAM via S-adenosyl-l-homocysteine (SAH). Further study revealed that conversion of SAM to SAH is facilitated by OxsB; however, the subsequent conversion of SAH to homocysteine is due to protein contaminants that co-purify with OxsA. Nevertheless, the observed demethylation of SAM to SAH suggests possible methyltransferase activity of OxsB, and substrate methylation was indeed detected in the OxsB-catalyzed reaction. This work is significant because it not only completes the description of the oxetanocin-A biosynthetic pathway but also suggests that OxsB may be capable of methyltransferase activity.

show abstract

“…Corrinoids without an upper ligand act as the catalytic center for reductive dehalogenases, in which the cobalt ion is thought to form a direct bond with the halide component of the substrate in order to mediate its abstraction (9). Finally, both methylcorrinoids and adenosylcorrinoids also appear to be involved in a specific group of radical SAM enzymes (6); B12radical SAM enzymes are the largest group within this broad enzyme class (10).…”

Section: Chlsmentioning

confidence: 99%

Biosynthesis of the modified tetrapyrroles—the pigments of life

Bryant

Hunter

Warren

2020

Journal of Biological Chemistry

199

164

View full text Add to dashboard Cite

Modified tetrapyrroles are large macrocyclic compounds, consisting of diverse conjugation and metal chelation systems and imparting an array of colors to the biological structures that contain them. Tetrapyrroles represent some of the most complex small molecules synthesized by cells and are involved in many essential processes that are fundamental to life on Earth, including photosynthesis, respiration, and catalysis. These molecules are all derived from a common template through a series of enzyme-mediated transformations that alter the oxidation state of the macrocycle and also modify its size, its side-chain composition, and the nature of the centrally chelated metal ion. The different modified tetrapyrroles include chlorophylls, hemes, siroheme, corrins (including vitamin B12), coenzyme F430, heme d1, and bilins. After nearly a century of study, almost all of the more than 90 different enzymes that synthesize this family of compounds are now known, and expression of reconstructed operons in heterologous hosts has confirmed that most pathways are complete. Aside from the highly diverse nature of the chemical reactions catalyzed, an interesting aspect of comparative biochemistry is to see how different enzymes and even entire pathways have evolved to perform alternative chemical reactions to produce the same end products in the presence and absence of oxygen. Although there is still much to learn, our current understanding of tetrapyrrole biogenesis represents a remarkable biochemical milestone that is summarized in this review.

show abstract

Cobalamin-dependent radicalS-adenosyl-l-methionine enzymes in natural product biosynthesis

Cited by 38 publications

References 88 publications

Genome mining- and synthetic biology-enabled production of hypermodified peptides

Genome mining- and synthetic biology-enabled production of hypermodified peptides

Biosynthesis of Oxetanocin-A Includes a B₁₂-Dependent Radical SAM Enzyme That Can Catalyze both Oxidative Ring Contraction and the Demethylation of SAM

Biosynthesis of the modified tetrapyrroles—the pigments of life

Contact Info

Product

Resources

About

Cobalamin-dependent radicalS-adenosyl-l-methionine enzymes in natural product biosynthesis

Cited by 38 publications

References 88 publications

Genome mining- and synthetic biology-enabled production of hypermodified peptides

Genome mining- and synthetic biology-enabled production of hypermodified peptides

Biosynthesis of Oxetanocin-A Includes a B12-Dependent Radical SAM Enzyme That Can Catalyze both Oxidative Ring Contraction and the Demethylation of SAM

Biosynthesis of the modified tetrapyrroles—the pigments of life

Contact Info

Product

Resources

About

Biosynthesis of Oxetanocin-A Includes a B₁₂-Dependent Radical SAM Enzyme That Can Catalyze both Oxidative Ring Contraction and the Demethylation of SAM