# Metalloenzyme structure, function, and as targets for neurodegeneration and bacterial pathogenesis

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $595,980

## Abstract

Heme is one of the most diverse and useful iron-containing cofactors in biology. One of
the most diverse functions are in oxidative heme enzymes that are designed to store the
oxidizing equivalents of H2O2 or O2 in order to carry out biologically useful oxidation
reactions. These include detoxification of toxic peroxides and xenobiotics (ie drug
metabolism) and the oxidation of small organic compounds in various biosynthetic
pathways such as in steroid metabolism and antibiotic biosynthesis. Structural biology
has played a critical role in understanding these enzymes and the Poulos lab has
focused primarily, but not exclusively, on peroxidases, cytochromes P450, nitric oxide
synthase (NOS), and the various auxiliary proteins required for electron transfer. Owing
to the transient nature of redox partner complexes, it has been difficult to determine
crystal structures which is why there are so few in the PDB. This gap in our knowledge is
especially important in P450s where redox partner binding can play a critical role in
controlling where the substrate is oxidized in addition to exerting an effector role critical
for proton coupled electron transfer. Recent advances in the well known P450cam
system has provided specific hypotheses on the structural changes induced by redox
partner binding that are required for O2 activation and has resulted in a rethinking of
traditional views on how P450s work. This has generated considerable discussion, some
quite controversial, but also has stimulated research to test the validity of some of these
new ideas. A critical question being addressed is the generality of redox partner effector
control in P450 catalysis in addition to the biological basis for why such a level of control
is required for some P450s but not others. NOS is a P450 and has provided deeper
insights into O2 activation and substrate oxidation. NOS also has proven to be an
important therapeutic target in neurodegenerative diseases and in certain pathogenic
bacteria like methicillin resistant Staph aureus (MRSA). Together with the Silverman lab
at Northwestern, structure-based methods are being applied to the development of
highly selective NOS inhibitors. Overall, the various ongoing projects provide a
synergistic mix of fundamental research in heme enzyme function with research having
clearly defined biomedical relevance.

## Key facts

- **NIH application ID:** 10406916
- **Project number:** 5R35GM131920-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** THOMAS L POULOS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $595,980
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406916

## Citation

> US National Institutes of Health, RePORTER application 10406916, Metalloenzyme structure, function, and as targets for neurodegeneration and bacterial pathogenesis (5R35GM131920-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10406916. Licensed CC0.

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