Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin K deficiency.
BACKGROUND
2-Methylacyl-CoA racemase interconverts the 2-methyl group of pristanoyl-CoA or the 25-methyl group of hydroxylated cholestanoyl-CoAs, allowing further peroxisomal desaturation of these compounds in man by the branched chain acyl-CoA oxidase, which recognise only the S-isomers. Hence, oxidation studies in fibroblasts, currently based on the use of racemic substrates such as [1-14C] pristanic acid, do not allow us to distinguish between a deficient racemase or an impaired oxidase.


METHODS
To evaluate the racemase activity directly, the 2R-isomer of[1-14C] pristanic acid, as well as the 2R-isomer of 2-methyl-[1-14C] hexadecanoic, a synthetic pristanic acid substitute, were prepared and their degradation by cultured human skin fibroblasts was compared to that of the racemic substrates.


RESULTS
In fibroblasts in a young girl, presenting with elevated urinary levels of trihydroxycholestanoic acid metabolites but normal plasma levels of very long chain fatty acids, a partial deficient degradation of racemic [1-14C] pristanic acid was observed. Incorporation of 2R-[1-14C] pristanic acid in glycerolipids of the patient's fibroblasts proceeded normally, but breakdown was impaired. Similar findings were seen with the 2R-isomer of 2-methyl-[1-14C] hexadecanoic. These data, combined with the fact that the branched chain acyl-CoA oxidase, catalyzing the first oxidation step of pristanic acid and bile acid intermediates in man, appeared normal, suggested a peroxisomal beta-oxidation defect in the patient at the level of 2-methylacyl-CoA racemase.


CONCLUSIONS
Carboxy-labelled 2R-methyl branched chain fatty acids might be useful tools to document cases of racemase deficiencies. Because a brother of the patient died with a diagnosis of vitamin K deficiency, an impaired racemase might be responsible for other cases of unexplicable malabsorption.
Van Veldhoven
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PP
Katholieke Universiteit Leuven, Afdeling Farmacologie, Leuven, Belgium. paul.vanveldhoven@med.kuleuven.ac.be
Meyhi
E
E
Squires
R H
RH
Fransen
M
M
Fournier
B
B
Brys
V
V
Bennett
M J
MJ
Mannaerts
G P
GP
D002478:Cells, Cultured; D005227:Fatty Acids / Q000138:chemical synthesis / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007536:Isomerism; D008286:Malabsorption Syndromes / Q000209:etiology*; D010084:Oxidation-Reduction; D010169:Palmitic Acids / Q000138:chemical synthesis / Q000378:metabolism; D018901:Peroxisomal Disorders / Q000201:enzymology*; D020675:Peroxisomes / Q000201:enzymology*; D019998:Racemases and Epimerases / Q000172:deficiency*; D012867:Skin / Q000166:cytology; D014813:Vitamin K Deficiency / Q000209:etiology*
D005227:Fatty Acids; D010169:Palmitic Acids; C034839:2-methylhexadecanoic acid; C002844:pristanic acid; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase