# Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $324,609

## Abstract

Project Summary
The goal of the proposed research is to elucidate fundamental physical-chemical
principles that govern catalysis in enzymes, with a focus on radical catalysis in
coenzyme B12 (adenosylcobalamin) –dependent enzymes. This goal will be
enacted through a program of biochemical and physical studies of
representatives of all three classes of B12 enzymes: methylmalonyl-CoA mutase
(MCM, Class I; human and Methylobacter extorquens), ethanolamine ammonia-
lyase (EAL, Class II; Salmonella typhimurium), and lysine-5,6-aminomutase
(Class III; LAM, Clostridium stricklandii). The approaches will be extended to
address molecular mechanism in the intracellular cobalamin (B12) trafficking
pathway in humans by the CblC and CblD proteins, and to the assembly and
function of the bacterial microcompartment (BMC), an in vivo context of the EAL
enzyme. Innovative methods, sofware and hardware for high-resolution pulsed-
electron paramagnetic resonance (EPR) spectroscopy, in parallel with time-
resolved, single-step reaction kinetics and steady-state solvent dynamics from
continuous-wave EPR methods, applied in unique, low-temperature systems, will
enable comprehensive characterization of the structural and dynamical
contributions of solvent-protein-reaction coupling to radical rearrangement
catalysis in the B12 enzymes. Significant biomedical and human health outcomes
include: (i) fundamental knowledge about the role of protein and coupled solvent
configurational states in enzyme function, latent at physiological temperatures,
that contribute new tools, models and targets to the developing roadmap for
leveraging these states in drug development and enzyme engineering, (ii)
characterization of EAL, a contributor to the role of the gut microbiome in human
health and disease progression, including links with inflammatory bowel disease,
obesity, and diabetes, (iii) characterization of the assembly and function of the
ethanolamine utilization (eut) BMC, one of a recently-recognized, widespread
class of primitive, protein-encased bacterial organelles, (iv) insights into the
molecular mechanistic basis of human metabolic disorders identified with the cbl
gene cluster, and in particular, the role of the human CblC (MMACHC,
methylmalonic aciduria type C and homocystinuria) and CblD proteins.

## Key facts

- **NIH application ID:** 10469587
- **Project number:** 5R01GM142113-21
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** KURT WARNCKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $324,609
- **Award type:** 5
- **Project period:** 1998-03-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469587

## Citation

> US National Institutes of Health, RePORTER application 10469587, Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis (5R01GM142113-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469587. Licensed CC0.

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