# Spectroscopic Studies of Molybdoenzymes & Models

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO · 2022 · $326,936

## Abstract

There exist fundamental gaps in the knowledge base regarding the final steps of molybdenum cofactor (Moco)
biosynthesis and sulfuration, how the Mo methionine sulfoxide reductase utilizes the pyranopterin dithiolene
component (MPT) of the cofactor in catalysis, and the role of non-MPT ligands in the catalytic cycles of
dimethylsulfoxide reductase family enzymes. Our long-term goal is to understand geometric and electronic
structure contributions to pyranopterin molybdenum enzyme reactivity and function in order to provide a positive
impact on the quality of human health. Our primary objectives are to determine critical Moco maturation, transport
and sulfuration steps, define the mechanism of MsrP and the role of the MPT in Msr mediated catalysis, and
understand the electronic structure of key paramagnetic intermediates in DMSOR family enzymes using a
combined spectroscopic approach augmented by detailed bonding, spectroscopic, and reaction coordinate
calculations. The central hypothesis is that specific geometric and electronic structure modifications of protein-
bound Moco define the unique reactions catalyzed. The rationale for this research is that a comprehensive
understanding of Moco maturation and transport, the complex interplay between Mo the MPT in Msr catalysis,
and the nature of paramagnetic DMSOR family intermediates will provide new insights into disease states and
have a positive impact on human health. We will test our central hypothesis in order to accomplish the objectives
of this proposal through the successful pursuit of three Specific Aims 1) Understand Moco maturation, transport,
and sulfuration, 2) Determine electronic structure contributions to MsrP catalysis, 3) Determine the electronic
and geometric structure of paramagnetic intermediates in DMSOR family enzymes. The proposed research is
innovative in its approach because we have integrated structural, multicomponent spectroscopic, and
computational investigations on models and enzymes to address critical questions concerning the final stages
of Moco biosynthesis and sulfuration, Mo catalyzed repair mechanisms for oxidatively damaged proteins, and
the synergistic interactions between MPT and amino acid ligation in pyranopterin Mo enzyme catalysis. This has
led to new insight into long-standing questions in the molybdoenzyme field, effectively opening new horizons for
future work in this area. The proposed research is significant since it will impact and advance our understanding
of molybdate insertion and post-translational sulfuration processes, sulfur and Moco trafficking, molybdoenzyme
mediated rescue of oxidatively damaged proteins, and the roles of amino acid and pyranopterin dithiolene ligands
in molybdoenzyme catalysis.

## Key facts

- **NIH application ID:** 10424499
- **Project number:** 5R01GM057378-24
- **Recipient organization:** UNIVERSITY OF NEW MEXICO
- **Principal Investigator:** MARTIN L KIRK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $326,936
- **Award type:** 5
- **Project period:** 1998-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424499

## Citation

> US National Institutes of Health, RePORTER application 10424499, Spectroscopic Studies of Molybdoenzymes & Models (5R01GM057378-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10424499. Licensed CC0.

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