Structure-based Phylogenetic Analysis of Short-chain Alcohol Dehydrogenases and Reclassification of the 17beta-Hydroxysteroid Dehydrogenase Family

Abstract

Short-chain alcohol dehydrogenases (SCAD) constitute a large and diverse family of ancient origin. Several of its members play an important role in human physiology and disease, especially in the metabolism of steroid substrates (e.g., prostaglandins, estrogens, androgens, and corticosteroids). Their involvement in common human disorders such as endocrine-related cancer, osteoporosis, and Alzheimer disease makes them an important candidate for drug targets. Recent phylogenetic analysis of SCAD is incomplete and does not allow any conclusions on very ancient divergences or on a functional characterization of novel proteins within this complex family. We have developed a 3D structure-based approach to establish the deep-branching pattern within the SCAD family. In this approach, pairwise superpositions of X-ray structures were used to calculate similarity scores as an input for a tree-building algorithm. The resulting phylogeny was validated by comparison with the results of sequence-based algorithms and biochemical data. It was possible to use the 3D data as a template for the reliable determination of the phylogenetic position of novel proteins as a first step toward functional predictions. We were able to discern new patterns in the phylogenetic relationships of the SCAD family, including a basal dichotomy of the 17beta-hydroxysteroid dehydrogenases (17beta-HSDs). These data provide an important contribution toward the development of type-specific inhibitors for 17beta-HSDs for the treatment and prevention of disease. Our structure-based phylogenetic approach can also be applied to increase the reliability of evolutionary reconstructions in other large protein families.

Structure-Based Phylogeny of the Metallo-β-Lactamases

“…Other normalizations of RMS distances in structural alignments have been used to construct structure-based phylogenies (4,5,16,22,26). In those studies the normalized RMS distances were used as the values in a distance matrix and distance-based phylogenies were constructed using unweighted pair group method with averages (UPGMA) or neighbor-joining methods.…”

Mitochondrial trans-2-Enoyl-CoA Reductase of Wax Ester Fermentation from Euglena gracilis Defines a New Family of Enzymes Involved in Lipid Synthesis

“…Additionally, two putative catalytic sites of the short-chain dehydrogenase/reductase family were identified in the TER amino acid sequence. Most proteins of this family possess a catalytic site with consensus motif YXXXK (37,40,41), and some show a modified motif with YX 3-7 K (42, 43). TER from Euglena possesses the motif YX 6 K at residues 231-238 and YX 5 K at residues 279 -285 (Fig.…”

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

“…However, opposite results have been reported, as in some studies the truncated HSD17B7 protein was found to be inactive (Marijanovic et al 2003). Owing to its amino acid sequence similarity with the yeast ERG27 protein, the HSD17B7 enzyme was also suggested to possess a 3-ketosteroid reductase activity (Breitling et al 2001a,b, Marijanovic et al 2003. Accordingly, in vitro, both the human and the mouse HSD17B7 enzymes have been shown to catalyse the conversion of zymosterone to zymosterol (Marijanovic et al 2003), an essential reaction in the cholesterol biosynthesis.…”