Functional Analysis of a Mosquito Short Chain Dehydrogenase Cluster.

JAIME G. MAYORAL; LEONARD, K; DEFELIPE, LA; A.G. TURJANSKI; MARCELA NOUZOVA; FERNANDO G. NORIEGA

INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2012

0965-1748

The short chain dehydrogenases (SDR) constitute one the oldest and largest families of enzymes with over 46,000 members in sequence databases. About 25% of all known dehydrogenases belong to the SDR family. SDR enzymes have critical roles in lipid, amino acid, carbohydrate, hormone and xenobiotic metabolism as well as in redox sensor mechanisms. This family is present in all domains of life, emphasizing their versatility and fundamental importance for metabolic processes. We identified a cluster of eight cP2 SDRs in the mosquito Aedes aegypti (AaSDRs). They are all NADP+-dependent and they have S-enantioselectivity and preference for secondary alcohols with 8-15 carbons. Members of the cluster differ in tissue specificity and developmental expression. Heterologous expression produced recombinant proteins that showed diverse substrate specificities, but distinct from the conventional insect alcohol (ethanol) dehydrogenases. Only AaSDR1 was able to process isoprenoid alcohols, including oxidation of farnesol into farnesal, a precursor of juvenile hormone (JH) in the corpora allata of mosquitoes. Homology modeling was used to build the structure of AaSDR1 and two additional cluster members. The computational study helped explain the selectivity towards the (10R)-isomers as well as the reduced activity of AaSDR4 and AaSDR9 for longer isoprenoid substrates. Similar clusters of SDRs are present in other species of insects, suggesting similar selection mechanisms causing duplication and diversification of this family of enzymes.