Comparatives study on sequence structure function relationship of human short -chain dehydrogenases/reductases

Abstract

The human short-chain dehydrogenases/reductases (SDRs) family has been the subject of many recent studies due to their crucial roles in the human body. There are a growing number of single-nucleotide polymorphisms and a variety of heritable metabolic diseases that have been identified from the SDR genome. Here, we carried out a phylogenetic analysis of homologous SDR sequences, and subsequently utilized a series of bio-informatics and comparative analytical methods to investigate the sequence-structure-function relationships within the human SDR family. Our findings show that Tyrosine, Serine, and Lysine are not only present in all members of the human SDR family, but are also located in a conserved region of both the SDR protein sequence and structure. In contrast, we find a cluster of three residues (Serine-Alanine-Serine, Phenylalanine-Glycine-Valine, Cystein-Serine-Serine, Cystein-Histidine-Serine or Alanine-Alanine-Alanine) that are different in protein sequence and structure and appear to be specific to each group of human SDR family. Finally, our analysis of correlated mutations within the human SDR family reveals the occurrence of residues that are distantly located, but seem to be interacting with one another. We hypothesize that these long-distance interactions may be an adaptive mechanism that allows members of the human SDR family to cope with a changing environment and differing functional demands over evolutionary time. Taken together, our results provide data that will be useful for designing inhibitors targeted at specific groups of human SDRs, such as those that are known to be metabolically disorders.

Key words: multiple sequence alignments, consensus sequence, phylogeny, mutational variability and correlation.