# Novel Mechanisms of Catalysis in Natural Product Biosynthesis > **NIH NIH R35** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $688,432 ## Abstract ABSTRACT Natural products offer a rich and plentiful source of novel compounds with biological activities from which fresh inspiration can be drawn for the discovery and design of new pharmaceuticals. Moreover, the rapid pace at which bioinformatic and genomic technologies are developing has led to a wealth of untested leads and intriguing questions regarding the biosynthetic pathways for these compounds. Enzymes utilizing radical intermediates are featured prominently here catalyzing chemical transformations that would otherwise not be possible under physiological conditions. Consequently, secondary metabolism is characterized by a multitude of unusual chemical structures rarely observed in primary metabolism. However, the instability of free radicals can easily lead such enzymatic reactions to go awry due to even minor perturbations. Not only does this suggest a mechanism for the evolution and diversification of radical-mediated transformations as proposed for radical SAM (S-adenosyl-L-methionine) enzymes but also implies that these enzymes may be engineered to catalyze similarly challenging transformations with applications in synthetic biology. In the spirit of helping to realize this potential, we have identified two primary areas of investigation with additional exploratory worked planned as well. The first direction involves study of the homologous pair of dehydratase and dehydrogenase twitch radical SAM enzymes BlsE and HikC, which respectively participate in the biosynthesis of the fungicide blasticidin S and antihelminthic agent hikizimycin. Given their evolutionary relationship, we hope to tease apart their catalytic properties in a comparative manner in order to understand how the fates of their radical intermediates are channeled to effect two distinctly different catalytic outcomes. The second direction focuses on biosynthesis of the antiviral nucleosides oxetanocin A and albucidin. Where one would normally expect a ribose, these natural products instead possess a four-membered oxetane ring that is constructed via radical-mediated transformations catalyzed by B12-dependent radical SAM enzymes. This chemistry is thus unique among the cobalamin- dependent radical SAM enzymes, which are primarily known to function as methyltransferases. These two projects are not only designed to offer new insights into the mechanisms of secondary metabolic enzymes that utilize radical intermediates but also to open new avenues of study. Nevertheless, a third component of the proposal is specifically designed to probe high risk systems including biosynthesis of the cis-fused cyclobutane ring system of ladderanes; a non-heme iron enzyme with a unique quadruple-histidyl/carboxylysyl coordination sphere newly discovered in the biosynthesis of oxazinomycin; as well as a radical SAM enzyme that catalyzes an unusual sulfur-for-oxygen bridge swapping reaction during biosynthesis of the Trojan horse antibiotic albomycin. Collectively our efforts are intended t... ## Key facts - **NIH application ID:** 10840701 - **Project number:** 1R35GM153203-01 - **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN - **Principal Investigator:** HUNG-WEN LIU - **Activity code:** R35 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $688,432 - **Award type:** 1 - **Project period:** 2024-06-01 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10840701 ## Citation > US National Institutes of Health, RePORTER application 10840701, Novel Mechanisms of Catalysis in Natural Product Biosynthesis (1R35GM153203-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10840701. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*