# Sulfide Oxidation and Signaling

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $69,512

## Abstract

Hydrogen sulfide (H2S), a signaling molecule that elicits profound physiological effects, is
a product of mammalian sulfur metabolism and is synthesized at relatively high rates. H2S
is biosynthesized by three enzymes in the sulfur network of which two, cystathionine beta-
synthase (CBS) and gamma-cystathionase, reside in the cytoplasmic transsulfuration
pathway while the third, mercaptopyruvate sulfurtransferase, is involved in cysteine
catabolism. Since H2S is highly toxic, cells avoid its build-up by an efficient oxidation
pathway that is housed in mitochondria and coupled to the energy-generating electron
transfer chain. The constituent proteins include sulfide-quinone oxidoreductase, a
persulfide dioxygenase, rhodanese and sulfite oxidase. While our studies on H2S
biogenesis are supported by HL58784, our work on H2S oxidation and signaling are
supported by GM130183. It is becoming increasing clear that the biosynthetic and
catabolic pathways for H2S interact and modulate each other. Therefore, the sulfide
research supported by HL58784, scheduled to expire this year, will be folded into and then
formally included in the competitive renewal of GM130183. In this supplemental project,
the following specific aims will be addressed to elucidate fundamental mechanisms of
regulation of H2S synthesis by CBS in normal and disease states: i) elucidate the steady
state kinetics of linker mutants in CBS in the canonical transsulfuration and non-canonical
H2S-generating reactions, (ii) investigate perturbations in the heme environment by EPR
spectroscopy and potentiometric titrations, (iii) assess the impact of the mutations on
AdoMet-dependent modulation of CO and NO• binding to ferrous heme and on the cellular
flux of sulfur, and (iv) crystallize the linker mutants that appear to be less prone to
aggregation compared to wild-type CBS. The impact of the proposed studies will be
fundamental (i.e. elucidating mechanims of allosteric regulation at the level of CBS and in
the pathway), medical (i.e. understanding the biochemical basis of failure of disease-
causing CBS mutations), and most importantly, training a URM scientist of high promise.

## Key facts

- **NIH application ID:** 10360743
- **Project number:** 3R35GM130183-03S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** RUMA V BANERJEE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $69,512
- **Award type:** 3
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360743

## Citation

> US National Institutes of Health, RePORTER application 10360743, Sulfide Oxidation and Signaling (3R35GM130183-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10360743. Licensed CC0.

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