Dataset Information

The Medium-Chain Dehydrogenase/reductase Engineering Database: a systematic analysis of a diverse protein family to understand sequence-structure-function relationship.

ABSTRACT: The Medium-Chain Dehydrogenase/Reductase Engineering Database (MDRED, http://www.mdred.uni-stuttgart.de) has been established to serve as an analysis tool for a systematic investigation of sequence-structure-function relationships. It includes sequence and structure information of 2684 and 42 medium-chain dehydrogenases/reductases (MDRs), respectively. Although MDRs are very diverse in sequence, they have a conserved tertiary structure. MDRs are assigned to 199 homologous families and 29 superfamilies. For each family, annotated multiple sequence alignments are provided, and functionally relevant residues are annotated. Twenty-five superfamilies were classified as zinc-containing MDRs, four as non-zinc-containing MDRs. For the zinc-containing MDRs, three subclasses were identified by systematic analysis of a variable loop region, the quaternary structure determining loop (QSDL): the class of short, medium, and long QSDL, which include 11, 3, and 5 superfamilies, respectively. The length of the QSDL is predictive for tetramer (short QSDL) and dimer (long QSDL) formation. The class of medium QSDL includes both tetrameric and dimeric MDRs. The shape of the substrate-binding site is highly conserved in all zinc-containing MDRs with the exception of two variable regions, the substrate recognition sites (SRS): two residues located on the QSDL (SRS1) and, for the class of long QSDL, one residue located in the catalytic domain (SRS2). The MDRED is the first online-accessible resource of MDRs that integrates information on sequence, structure, and function. Annotation of functionally relevant residues assist the understanding of sequence-structure-function relationships. Thus, the MDRED serves as a valuable tool to identify potential hotspots for engineering properties such as substrate specificity.

SUBMITTER: Knoll M

PROVIDER: S-EPMC2548362 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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The Medium-Chain Dehydrogenase/reductase Engineering Database: a systematic analysis of a diverse protein family to understand sequence-structure-function relationship.

Knoll Michael M Pleiss Jürgen J

Protein science : a publication of the Protein Society 20080709 10

The Medium-Chain Dehydrogenase/Reductase Engineering Database (MDRED, http://www.mdred.uni-stuttgart.de) has been established to serve as an analysis tool for a systematic investigation of sequence-structure-function relationships. It includes sequence and structure information of 2684 and 42 medium-chain dehydrogenases/reductases (MDRs), respectively. Although MDRs are very diverse in sequence, they have a conserved tertiary structure. MDRs are assigned to 199 homologous families and 29 superfa ...[more]

PMID: 18614751

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Project description:All-trans-retinoic acid (RA) is a bioactive derivative of vitamin A that serves as an activating ligand for nuclear transcription factors, retinoic acid receptors. RA biosynthesis is initiated by the enzymes that oxidize retinol to retinaldehyde. It is well established that retinol dehydrogenase 10 (RDH10, SDR16C4), which belongs to the 16C family of the short chain dehydrogenase/reductase (SDR) superfamily of proteins, is the major enzyme responsible for the oxidation of retinol to retinaldehyde for RA biosynthesis during embryogenesis. However, several lines of evidence point towards the existence of additional retinol dehydrogenases that contribute to RA biosynthesis in vivo. In close proximity to RDH10 gene on human chromosome 8 are located two genes that are phylogenetically related to RDH10. The predicted protein products of these genes, retinol dehydrogenase epidermal 2 (RDHE2, SDR16C5) and retinol dehydrogenase epidermal 2-similar (RDHE2S, SDR16C6), share 59% and 56% sequence similarity with RDH10, respectively. Previously, we showed that the single ortholog of the human RDHE2 and RDHE2S in frogs, Xenopus laevis rdhe2, oxidizes retinol to retinaldehyde and is essential for frog embryonic development. In this study, we explored the potential of each of the two human proteins to contribute to RA biosynthesis. The results of this study demonstrate that human RDHE2 exhibits a relatively low but reproducible activity when expressed in either HepG2 or HEK293 cells. Expression of the native RDHE2 is downregulated in the presence of elevated levels of RA. On the other hand, the protein encoded by the human RDHE2S gene is unstable when expressed in HEK293 cells. RDHE2S protein produced in Sf9 cells is stable but has no detectable catalytic activity towards retinol. We conclude that the human RDHE2S does not contribute to RA biosynthesis, whereas the low-activity RA-sensitive human RDHE2 may have a role in adjusting the cellular levels of RA in accord with specific physiological conditions.

Dataset Information

The Medium-Chain Dehydrogenase/reductase Engineering Database: a systematic analysis of a diverse protein family to understand sequence-structure-function relationship.

Publications

The Medium-Chain Dehydrogenase/reductase Engineering Database: a systematic analysis of a diverse protein family to understand sequence-structure-function relationship.

Similar Datasets

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