Bacterial Mercapturic Acid Metabolites

Mercapturic acid metabolites or N-acetylcysteine adducts are recognized mammalian detoxification products. However, the capacity of Actinobacteria to produce mercapturic acid metabolites is not broadly known, even though the first bacterial metabolite of this type was reported over 30 years ago [1]. Interestingly, even though the mammalian and bacterial final products all have N-acetylcysteine attached to a molecule through the sulfur atom, in Actinobacteria the adducts do not arise from glutathione attack on a reactive species, but rather via the participation of a glutathione equivalent, mycothiol. Mycothiol is N-acetylcysteine linked by an amide bond to glucosamine, which has a glycosidic linkage to inositol [2]. As with glutathione adducts, the initial mycothiol adducts are enzymatically cleaved to yield the mercapturic acid products. In most natural products isolation and structure elucidation articles reporting these compounds, this processing of the initial mycothiol adduct is not mentioned, but instead the bacterial mercapturic acid metabolites have been attributed to mixed biosynthetic pathways or activation of additional genes in heterologous hosts. These molecules are often considered to be new secondary metabolites or “true” natural products, but evidence is mounting that these are actually biotransformation products resulting from the bacterium protecting itself from a reactive electrophilic species produced in excess. A variety of examples will be provided demonstrating the diversity of molecules, mainly polyketide to date, that are modified with N-acetylcysteine. In several cases the electrophilic precursor has been established chemically, but in each case a reactive precursor can be envisioned. As illustrated by the examples provided, Actinobacteria can produce mercapturic acid metabolites in a manner that parallels the detoxification process in human drug biotransformation.

Keywords: Biotransformation; detoxification; acetylcysteine adduct; mercapturic acid adduct.

References:

[1] Kormann E, Pape H. Modification of the antibiotic granaticin A by the producting organism Streptomyces violaceoruber Tü 7. Third Eur Congr Biotechnol 1984; 1:105 – 109

[2] Jothivasan VK, Hamilton, CJ. Mycothiol: synthesis, biosynthesis and biological functions of the major low molecular weight thiol in actinomycetes. Nat Prod Rep 2008; 25:1091 – 1117