DHRS1 Discussion

Structure

The SDR family have highly conserved structural features in particular the NAD(P) binding site, central β-strand and co-enzyme binding site.

Structural alignments with other members of the SDR family showed that the most closely structurally related proteins were all involved in reducing substrates (reductases). In particular Glucose reductases appeared frequently (Table 1). All of the protiens that had high structural similarity existed as dimers, tetramers or octamers, indicating that DHRS1 also exists as more than a monomer biologically. Most of the protiens in the SDR family act in tandem with co-enzymes and a highly conserved motif [G-x(3)-G-x-G] that is thought to be a co-enzyme binding site (Wu Q, et al 2001) is also present in DHRS1.

DHRS1 has been crystallized to a resolution of 1.8 Å with an R-value of 0.159. This R-value however was achieved without recording a highly mobile region of 22 amino acids which covers over the NAD(P) binding site, and may act as a cap protecting the NAD(P) binding site when the enzyme is not in use. This flexible region also covers part of the co-enzyme binding site indicating that this region moves when the enzyme is biologically active.

Sequence

The Short chain dehydrogenase family has evolved over a long period of time and has two main forms, classical SDR and extended SDR.

Classic SDR is primarily found in bacteria and is approximately 250 amino acids long and appears to have evolved first, extended SDR's are typically 350 amino acids long and have evolved later. The sequence identity for this family is low, approdimately 15 to 20%, This is due to the age of the family and has lead to many point mutations, which have been incorporated over time when the mutation is not fatal to the organism.

One of the mutations incorporated over time is for a subgroup of the family including land based higher organisms such as humans, monkeys, dogs, cats and cows. This is identified by an inserted motif K-[A,S]-F-W-E-x-P-A-S at location 138 - 146. This region does not exist in the classic SDR family and shows variation in the extended family, although is completely conserved within organisms such as those named earlier. The extended SDR family includes some proteobacteria and all the sequences of the anamalia kingdom with the exception of Aedes aegypti. This subgroup suggests that the extended SDR family evolved from the classic SDR family and has continued to evolve. It also suggests that this family was incorporated into higher organisms after this evolution to the extended SDR.

Aedes aegypti was the only eukaryote which incorporated the classic SDR protein in our phylogenetic tree. It is possible that this is due to this particular organisms parasitic nature and this may have increased the oppertunity for lateral gene transfer to occur. It is possible that this organism did not have the ability to process glucose prior to incorporating this gene from a transfer event and due to this event had a significant evolutionary advantage, causing this protein to be conserved in the organism after transfer.

Function

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