# MOLECULAR GENETIC STUDIES ON METHYLMALONYL MUTASE

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 1994 · $164,842

## Abstract

This application is a continuation of our FIRST award with the same
title.  Our PROGRESS REPORT describes molecular genetic studies aimed at
cloning and characterizing cDNAs for human and mouse methylmalonyl CoA
mutase (MCM) cDNAs, the genomic loci (MUT, mut) encoding MCM, and
mutations causing distinctive phenotypes of MCM deficiency.  We have
established methods for gene transfer into primary fibroblasts and S.
ceriviseae and used these systems to characterize functional defects in
mutant gene products and the biological response to overexpression of
MCM.  This proposal focuses on applying molecular methods to answer
questions raised by our ongoing work concerning the dynamic role of MCM
in metabolic flux, homeostasis, and disease.  This work will focus on
three questions.  How do mutations in MCM affect enzyme activity?
Mutation analysis has delineated two independent functional domains in
MCM: one involved in cobalamin binding domain, and a second with
undetermined function which participates in interallelic complementation.
We will identify select mutations to assess the location and function of
other domains within MCM and explore the relationship between the
genotype and the biochemical or clinical phenotype of MCM deficiency.
What mechanisms regulate the level of enzyme activity? Preliminary
studies have identified several mechanisms which may determine the level
of MCM activity.  We will further assess the pattern of tissue specific
expression of MCM mRNA as well as the role of sequences in the promoter
and cDNA which may affect transcriptional or translational regulation of
MCM.  How does regulation of MCM enzyme activity and mutations in MCM
affect metabolic flux through MCM? We have demonstrated that the level
of MCM enzyme activity does not normally limit flux of metabolites from
propionate through MCM in fibroblasts.  We will study the relationship
between MCM enzyme activity and metabolic flux through MCM in hepatoma
cells by overexpressing recombinant MCM and inhibiting endogenous enzyme
expression with antisense constructs.  We will investigate whether MCM
has a different kinetic role in metabolic flux from amino acids compared
to propionate or methylmalonate.  Finally, we will investigate the
mechanism for the observation that some mutant alleles inhibit propionate
flux through MCM in the presence of higher than normal levels of MCM
enzyme activity; an observation which suggests that MCM may be a
component of a larger multi-enzyme complex with a critical role in
determining the capacity for propionate metabolism.  These studies are
intended to provide a dynamic understanding of the role of MCM in
metabolic flux and homeostasis as well as the consequences of MCM
deficiency.

## Key facts

- **NIH application ID:** 2199070
- **Project number:** 5R01HD024186-07
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **SAM.gov UEI:** FXKMA43NTV21
- **Principal Investigator:** FRED D LEDLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $164,842
- **Award type:** 5
- **Project period:** 1988-06-01 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2199070

## Citation

> US National Institutes of Health, RePORTER application 2199070, MOLECULAR GENETIC STUDIES ON METHYLMALONYL MUTASE (5R01HD024186-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2199070. Licensed CC0.

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