Dicarboxylic acids are prominent features of several diseases, including
Reye's syndrome and inborn errors of mitochondrial and peroxisomal
fatty acid oxidation. Moreover,
dicarboxylic acids are potentially toxic to cellular processes. Previous studies [Tonsgard, Mendelson & Meredith (1988) J. Clin. Invest. 82, 1567-1573] demonstrated that long-chain
dicarboxylic acids have a single high-affinity binding site and between one and three lower-affinity sites on
albumin. Medium-chain-length
dicarboxylic acids have a single low-affinity site. We further characterized dicarboxylic
acid binding to
albumin in order to understand the potential effects of drugs and other
ligands on dicarboxylic
acid binding and toxicity.
Progesterone and
oleate competitively inhibit octadecanedioic
acid binding to the single high-affinity site.
Octanoate inhibits binding to the low-affinity sites. Dansylated probes for subdomain 2AB inhibit
dodecanedioic acid binding whereas probes for subdomain 3AB do not. In contrast, low concentrations of octadecanedioic
acid inhibit the binding of dansylated probes to subdomain 3AB and 2AB.
L-Tryptophan, which binds in subdomain 3AB, inhibits
hexadecanedioic acid binding but has no effect on
dodecanedioic acid.
Bilirubin and
acetylsalicylic acid, which bind in subdomain 2AB, inhibit the binding of medium-chain and long-chain
dicarboxylic acids. Our results suggest that long-chain
dicarboxylic acids bind in subdomains 2C, 3AB and 2AB. The single low-affinity binding site for medium-chain
dicarboxylic acids is in subdomain 2AB. These studies suggest that
dicarboxylic acids are likely to be unbound in disease states and may be potentially toxic.