Document Detail

Glutaconyl-CoA is the main toxic agent in glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).
MedLine Citation:
PMID:  15922108     Owner:  NLM     Status:  MEDLINE    
Despite early diagnosis and treatment, 35% of the patients with glutaric aciduria type I (GA I) develop severe neurologic damage. Glutaric acid and 3-hydroxyglutaric acid have been suspected to cause neurodegeneration. Lately, this has been questioned, however. We postulate that glutaconyl Coenzyme A (glutaconyl-CoA) is responsible for brain damage. Chemically, glutaconyl-CoA is an analogue of acrylyl-CoA, the parent substance of the extremely reactive class of acrylates. It is expected to react spontaneously with sulfhydryl groups, thus modifying membranes, disturbing enzyme functions and trapping glutathione. Enhanced production of glutaconyl-CoA together with lack of glutathione precipitates brain damage. Such a mechanism is supported by three findings. (1) The addition product of glutaconyl-CoA to cysteine is present in small amounts in normal human urine. (2) Reaction of methacrylyl-CoA with free sulfhydryl groups has been reported previously in a patient with 3-hydroxyisobutyryl CoA deacylase deficiency. (3) Glutathione has been found to be decreased in homozygous glutaryl-CoA dehydrogenase-deficient knock-out mice.
Willy Lehnert; Jörn Oliver Sass
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Medical hypotheses     Volume:  65     ISSN:  0306-9877     ISO Abbreviation:  Med. Hypotheses     Publication Date:  2005  
Date Detail:
Created Date:  2005-05-30     Completed Date:  2005-09-16     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  7505668     Medline TA:  Med Hypotheses     Country:  Scotland    
Other Details:
Languages:  eng     Pagination:  330-3     Citation Subset:  IM    
Stoffwechsellabor, Zentrum für Kinderheilkunde- und Jugendmedizin, Universitätsklinikum Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany.
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MeSH Terms
Acyl Coenzyme A / pharmacology*
Amino Acid Metabolism, Inborn Errors / metabolism
Brain / metabolism
Cysteine / chemistry
Glutaryl-CoA Dehydrogenase
Glutathione / metabolism
Mice, Knockout
Models, Chemical
Models, Theoretical
Oxidoreductases Acting on CH-CH Group Donors / deficiency*
Reg. No./Substance:
0/Acyl Coenzyme A; 52-90-4/Cysteine; 6712-05-6/glutaconyl-coenzyme A; 70-18-8/Glutathione; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC Dehydrogenase

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