Medium- and short-chain dehydrogenase/reductase gene and protein families: The MDR superfamily

The MDR superfamily with ~350-residue subunits contains the classical liver alcohol dehydrogenase (ADH), quinone reductase, leukotriene B4 dehydrogenase and many more forms. ADH is a dimeric zinc metalloprotein and occurs as five different classes in humans, resulting from gene duplications during vertebrate evolution, the first one traced to ~500 MYA (million years ago) from an ancestral formaldehyde dehydrogenase line. Like many duplications at that time, it correlates with enzymogenesis of new activities, contributing to conditions for emergence of vertebrate land life from osseous fish. The speed of changes correlates with function, as do differential evolutionary patterns in separate segments. Subsequent recognitions now define at least 40 human MDR members in the Uniprot database (corresponding to 25 genes when excluding close homologues), and in all species at least 10888 entries. Overall, variability is large, but like for many dehydrogenases, subdivided into constant and variable forms, corresponding to household and emerging enzyme activities, respectively. This review covers basic facts and describes eight large MDR families and nine smaller families. Combined, they have specific substrates in metabolic pathways, some with wide substrate specificity, and several with little known functions

The short-chain dehydrogenase/reductase nomenclature initiative.

The short-chain dehydrogenase/reductases (SDR) comprise a large superfamily of NAD(P)(H)-dependent oxidoreductases which are distinct from the medium-chain dehydrogenase (MDH) and aldo-keto reductase (AKR) superfamilies. They are expressed across all phyla, there are over 15,000 primary structures annotated in the various sequence databases, and over 139 crystal structures exist in the protein data bank. The majority of these proteins have low sequence identity, but share common sequence motifs that define the cofactor binding-site (TGxxxGxG), which is present in a central β-sheet, and the catalytic residues (N-S-Y-K). Three-dimensional SDR protein structures also share a common α/β-folding pattern characterized by a central β-sheet typical of a Rossmann-fold with helices on either side. In humans at least 63 SDR genes exist, where they play physiological roles in steroid hormone, prostaglandin and retinoid metabolism and hence signaling. SDRs also play important roles in the metabolism of xenobiotics, drugs and carcinogens. A growing number of single-nucleotide polymorphisms have been assigned to SDR genes. As this field continues to grow, the need for a systematic nomenclature is essential for annotation and reference purposes. Such a system would prevent either the same protein or gene being given multiple names or the same name being given to multiple proteins or genes. We have formed a working group to make recommendations on SDR nomenclature. A number of preliminary recommendations have been made: first the system should be gene rather than protein-based; second, the system should be expandable to accommodate new members as they are discovered; third, as members of the SDR superfamily cluster into minimally five families: “extended (E)”, “classical (C)”, “intermediate (I)”, “divergent (D)” and “undefined (U)” these should represent the major sub-categories. Thus a gene would be assigned to the SDRE, SDRC, SDRI, SDRD or SDRU families. Fourth, the nomenclature system will be webbased and detailed on an SDR Homepage which will contain information similar to that found on the AKR superfamily homepage at: www. med.upenn.edu/akr, as well as being disseminated throughout the major gene and protein databases. Additional recommendations on the proposed nomenclature will be presented

The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative

Short-chain dehydrogenases/reductases (SDR) constitute one of the largest enzyme superfamilies with presently over 46,000 members. In phylogenetic comparisons, members of this superfamily show early divergence where the majority have only low pairwise sequence identity, although sharing common structural properties. The SDR enzymes are present in virtually all genomes investigated, and in humans over 70 SDR genes have been identified. In humans, these enzymes are involved in the metabolism of a large variety of compounds, including steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. It is now clear that SDRs represent one of the oldest protein families and contribute to essential functions and interactions of all forms of life. As this field continues to grow rapidly, a systematic nomenclature is essential for future annotation and reference purposes. A functional subdivision of the SDR superfamily into at least 200 SDR families based upon hidden Markov models forms a suitable foundation for such a nomenclature system, which we present in this paper using human SDRs as examples

A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells

Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs may regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent, and selective inhibitors of key ALDH enzymes may represent a novel CSC-directed treatment paradigm for ALDH+ cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, our structure of human ALDH1A3 combined with in silico modeling identifies a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis reveals that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation