SIRT5 restores activity of GCDH

Some OAT results show elevated 3-hydroxyglutaric acid, and it’s usually assumed that this marker and glutaric acid marker indicate FAD (vitamin B2) deficiency.

While this can be true in many cases, there is one more reason for the elevation of these two markers - reduced activity of SIRT5 enzyme. This may indicate significant NAD deficiency (vitamin B3) or other reasons when either expression of GCDH or SIRT5 are not sufficient:

Here, we identify glutarylation on the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH) and show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism.

Our data reveal that glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We also demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity.

Finally, metabolomic and bioinformatic analyses indicate an expanded role for SIRT5 in regulating amino acid metabolism. Together, these data support a feedback loop model within the lysine/tryptophan oxidation pathway in which glutaryl-CoA is produced, in turn inhibiting GCDH function via glutaryl modification of GCDH lysine residues and can be relieved by SIRT5 deacylation activity. (R1)