2024-03-28T18:35:02Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1626402022-10-06T11:14:47Zcom_10261_86com_10261_1col_10261_339
Fungal metabolic model for 3-methylcrotonyl-CoA carboxylase deficiency
Rodríguez, José M.
Ruiz-Sala, Pedro
Ugarte, Magdalena
Peñalva, Miguel Ángel
Dirección General de Investigación Científica y Técnica, DGICT (España)
Instituto de Salud Carlos III
10 p.-8 fig.
Aspergillus nidulans is able to use Leu as the sole carbon source through a metabolic pathway leading to acetyl-CoA and acetoacetate that is homologous to that used by humans. mccA and mccB, the genes encoding the subunits of 3-methylcrotonyl-CoA carboxylase, are clustered with ivdA encoding isovaleryl-CoA dehydrogenase, a third gene of the Leu catabolic pathway, on the left arm of chromosome III. Their transcription is induced by Leu and other hydrophobic amino acids and repressed by glucose. Phenotypically indistinguishable DeltamccA, DeltamccB, and DeltamccA DeltamccB mutations prevent growth on Leu but not on lactose or other amino acids, formally demonstrating in vivo the specific involvement of 3-methylcrotonyl-CoA carboxylase in Leu catabolism. Growth of mcc mutants on lactose plus Leu is impaired, indicating that Leu metabolite(s) accumulation resulting from the metabolic block is toxic. Human patients carrying loss-of-function mutations in the genes encoding the subunits of 3-methylcrotonyl-CoA carboxylase suffer from methylcrotonylglycinuria. Gas chromatography/mass spectrometry analysis of culture supernatants revealed that fungal Deltamcc strains accumulate 3-hydroxyisovaleric acid, one of the diagnostic compounds in the urine of these patients, illustrating the remarkably similar consequences of equivalent genetic errors of metabolism in fungi and humans. We use our fungal model(s) for methylcrotonylglycinuria to show accumulation of 3-hydroxyisovalerate on transfer of 3-methylcrotonyl-CoA carboxylase-deficient strains to the isoprenoid precursors acetate, 3-hydroxy-3-methylglutarate, or mevalonate. This represents the first reported genetic evidence for the existence of a metabolic link involving 3-methylcrotonyl-CoA carboxylase between isoprenoid biosynthesis and Leu catabolism, providing additional support to the mevalonate shunt proposed previously (Edmond, J., and Popják, G. (1974) J. Biol. Chem. 249, 66-71).
This work was supported by Dirección General de Investigación Científica y Técnica Grant 2FD97-1292 and Fondo de Investigaciones Sanitarias Grant G03/054, respectively.
Peer reviewed
2018-03-21T12:44:05Z
2018-03-21T12:44:05Z
2004-02-06
artículo
http://purl.org/coar/resource_type/c_6501
J Biol Chem 279(6):4578-87 (2004)
0021-9258
http://hdl.handle.net/10261/162640
10.1074/jbc.M310055200
1083-351X
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100008737
en
Publisher's version
http://dx.doi.org/10.1074/jbc.M310055200
Sí
open
American Society for Biochemistry and Molecular Biology