# Understanding and manipulating biosynthetic mechanisms for formation of terpenes relevant to human health

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $371,293

## Abstract

The Tantillo group applies modern computational chemistry to elucidate and manipulate the
mechanisms by which terpenes (natural products derived from isoprene oligomers) and
terpenoids (functionalized terpenes) are produced in nature. Techniques employed range from
quantum chemistry to automated docking augmented by chemically meaningful constraints. The
terpene/terpenoid class of natural products is the largest and most diverse in terms of both
structures and biological activities relevant to humans (e.g., anti-cancer, anti-inflammatory,
analgesic, anti-convulsive, anti-depressant, neuroprotective, anti-allergic, antibiotic, and others).
The overall vision for the research program is to rationally expand the chemical space of terpenes
and terpenoids using mechanistic insights obtained from computaional chemistry experiments,
thereby providing new input for the testing and development of terpene-like compounds with
potential new biological activities. A bottom-up modeling approach will be employed in which
specific contributions to catalysis and selectivity are assessed using a series of theoretical
experiments designed to reduce complicating factors (i.e., we will characterize inherent reactivity
in the absence of an enzyme using quantum chemistry, then model specific enzyme-substrate
interactions, then model the effect of active site shape using methods developed in-house that
are specific for terpene synthases). Our predictions will be put to the test via synthesis of methyl-
edited substrates and characterization of their reactions with terpene synthases we design. In
addition to providing access to new terpene synthase enzymes that produce terpene-like
molecules with new carbon skeletons and methylation patterns that can be tested for biological
activity, this multi-step, multi-scale modeling approach will hopefully transform how computational
studies on cyclization/rearrangement-promoting enzymes are generally carried out, in that it
avoids the many issues associated with assessing contributions associated with specific effects
from simulations that involve entire enzyme-substrate systems alone.

## Key facts

- **NIH application ID:** 10842671
- **Project number:** 1R35GM153469-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Dean Tantillo
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $371,293
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842671

## Citation

> US National Institutes of Health, RePORTER application 10842671, Understanding and manipulating biosynthetic mechanisms for formation of terpenes relevant to human health (1R35GM153469-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842671. Licensed CC0.

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