Are class III alcohol dehydrogenases the ancestral group inside the medium‐chain dehydrogenase/reductase superfamily?

Glutathione‐dependent formaldehyde dehydrogenase activity of class III alcohol dehydrogenase (ADH) has been proposed as the ancient activity from which both animal and plant ADH are derived. However, Zinc‐dependent ADHs, (today named preferentially as medium‐chain dehydrogenases/reductases, MDRs) constitutes a large superfamily of enzymes with almost 1000 members occurring in all types of organisms. Because in a previous work [Eur J Biochem (2003) 270:3309] we showed that MDRs protein members are sorted in 3 protein macrofamilies, 8 families and 50 subfamilies, the role of class III ADH as the ancestral activity inside the MDR superfamily remains uncertain. Therefore, we performed a phylogenetic analysis including both eukaryotic and non‐eukaryotic protein sequences from class III ADH and related protein subfamilies, to test their role as the ancestral group for MDR superfamily. The obtained results show that MDRs possess a universal distribution, which contrast with the restricted distribution of glutathione, present only in proteobacteria, cyanobacteria, and eukaryotes. Furthermore, organisms without glutathione possess in any case MDR protein members with formaldehyde dehydrogenase activity either as cofactor‐independent (archaea) or mycothiol‐dependent (firmicutes). Thus, data suggest that formaldehyde dehydrogenase activity in MDRs predates the origin of glutathione or mycothiol. Supported by CONACYT‐México grant 45003M and DGAPA‐UNAM grant IN224206‐2.