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Retinal Dehydrogenase Type Two Structure

This molecular structure is Retinal Dehydrogenase Type Two (RalDH2) which was extracted from Rattus norvegicus.^[1] The sample was a crystallization of a clone of RalDH2 that was given as a gift from J. L. Napoli. It has been shown that RalDH2, the cellular binding protein type I, and the retinol binding protein receptor all co-localize in tissues that require Vitamin A (retinol) for normal development in rat embryos post-gastrulation, as discussed by "personal communication" to the authors of the "The Structure of Retinal Dehydrogenase Type II at 2.7 Angstrom Resolution: Implications for Retinal Specificity".^[1] This enzyme is part of the super family Aldehyde Dehydrogenase. The function of this enzyme is to catalyze the oxidation of retinal to retinoic acid. Retinoic acid produces a putative morphogen that initiates pattern formation in the early embryo.^[1] This is the last step in the formation of the hormone from Vitamin A (retinol).^[1] Vitamin A that has been metabolized can produce retinoid derivatives which function in either vision or growth and development. ^[2] RalDH2 is expressed in Escherichia coli strain BL21(DE3) ^[3]

Function

The main function of this enzyme is to Retinoic acid. RalDH2 requires (NAD+) as a cofactor.^[1] In the oxidoreductase reaction, NAD+ acts as an electron acceptor. The reaction of this enzyme is [(retinal) + (NAD+) + (H2O) ↔ (retinoic acid) + (NADH) + (H+) ]. Once the NAD+ is bound, hydrogen bonds form with non-polar residues and one basic Lysine residue. Chloride ions participate in hydrophobic interactions with Arginine residues.^[1] Theres interactions cause a structural change to occur in the RalDH2 enzyme which causes it to form a more favorable folded confirmation. In the enzyme a large binding cavity is formed. tructural changes occur to stabilize the tertiary structure of RalDH2

Structural highlights

Figure 1 Nucleotide-binding domain - orange, Catalytic domain - green, Tetramerization domain - blue. Imagine modified in Chimera from (PDB entry 1bi9). Chain D shown with NAD substrate shown in pink

Figure 3 Section (a) is the dimer of RalDH2 with the green spheres representing the amino and carboy termini of the substrate access channel loop. Section (b) shows the same orientation as section (a) with both dimers present and then the two dimers spun 90 degrees on the X-axis

The structure was based on the mitochondrial aldehyde dehydrogenase type two. RalDH2 in a monomer made up of 3 domains: a nucleotide-binding domain (1-136, 161-270), a catalytic domain (271-484), and a tetramerization domain (137-160, 485-484) as shown in Figure 1.^[1] The tetramer can be envisioned as an "X", with nucleotide-binding sites at the tips of the "X", and the tetramerization domains as the equatorial portion of the "X" as seen in Figure 2.^[1] In Figure 3 it is possible to see the active site, which is where the substrate interacts with Cys-302.

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Substrate NAD

The crystal structure was cocrystallized with , and was determined at a 2.7 Angstrom resolution. ^[1]

Disease

Relevance

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References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8} Lamb AL, Newcomer ME. The structure of retinal dehydrogenase type II at 2.7 A resolution: implications for retinal specificity. Biochemistry. 1999 May 11;38(19):6003-11. PMID:10320326 doi:10.1021/bi9900471
2. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Families_of_Retinoic_Dehydrogenases
3. ↑ Lamb AL, Wang X, Napoli JL, Newcomer ME. Purification, crystallization and preliminary X-ray diffraction studies of retinal dehydrogenase type II. Acta Crystallogr D Biol Crystallogr. 1998 Jul 1;54(Pt 4):639-42. PMID:9761861