A Prosthetic Reaction for Homocystinuria

Bhimani, Mira

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https://hdl.handle.net/2142/133271 Copy

Description

Title

A Prosthetic Reaction for Homocystinuria

Author(s)

Bhimani, Mira

Issue Date

2026-05-14

Director of Research (if dissertation) or Advisor (if thesis)

• Burke, Martin
• Meyle, Elisia

Department of Study

Chemistry

Degree Granting Institution

University of Illinois Urbana Champaign

Degree Name

B.S. (bachelor's)

Degree Level

Thesis

Date of Ingest

2026-05-14T09:46:06-05:00

Keyword(s)

Homocystinuria, cystathionine beta synthase, molecular prosthetics

Language

eng

Abstract

Homocystinuria is a rare genetic disorder characterized by elevated levels of homocysteine, an intermediate product of methionine metabolism. Accumulation of homocysteine leads to toxic effects in the eyes, bones, brain, and heart. While acquired cases can result from dietary vitamin B deficiencies, the most common form, classical homocystinuria, is caused by a genetic deficiency in the cystathionine -cynthase (CBS) enzyme. We hypothesized that a rationally designed small molecule electrophile could react directly with elevated levels of homocysteine to convert it to cystathionine, thus replacing the function of the missing CBS enzyme, and restoring physiology. An ideal prosthetic reagent should be non-toxic, selective for thiols over other nucleophiles, and selective for homocysteine over other amino acids and proteins. We evaluated the reactivity of candidate electrophiles containing -lactone, aziridine, and acrylamide motifs with homocysteine. We further tested the best performing compounds for their selectivity, toxicity, and kinetics. In addition, we synthesized derivatives or our lead compound for structure-activity relationship (SAR) studies to understand and optimize the reactivity of the molecule, with the long-term goal of developing a small molecule prosthetic reagent for CBS deficiency in homocystinuria.

Type of Resource

text

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