DHRS1 Discussion

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, approximately 15 to 20%, This is due to two main reasons, firstly the relatively low number of highly conserved sequences, for example only 4 regions, totaling 8 residues are involved in the ATP binding site, and even within these regions there is some variation of the specific residue, although it is heavily restrained to within the certain groups of amino acids with similar properties and is still almost always conserved to the same residue in these important sites. These sites are infrequent and most of the residues are variable without any significant change in structure or function. Secondly this is partially 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.

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.

Function

To date, functional studies of DHRS1 have been limited and inconclusive. However, some appropriate hypothesises can be formulated by comparing both structural and evolutionary similarities between DHRS1 and other similar known proteins.

DHRS1 is a member of the SDR family, which although shows low sequence homology, still has conserved domains. SDR family members can be sub-categorised into sub-families from motif similarities. Classical, extended, intermediate, divergent and complex, are all defined by a sequence motif(s). This should mean that studies relating to other similar sub-family proteins should offer insight into roles of DHRS1. Classical SDR family members share the following: [ILV]TGx(3)[AG][FILV]Gx(3)[AS]x(2)[FILMV]x(3)Gx(2)[ILMV] which is found from V12 to L25 in DHRS1. (Kallberg et al. 2002b). This suggest that it is a classical SDR. Kallberg

The most important consevered motif is the NAD/NADP (Nicotinamide adenine dinucleotide (phosphate)) binding site as this reserves its function. (F) NAD and NADP as well as their variants have roles in metabolism, whether it is fatty acid metabolism, energy metabolism or reductive biosynthesis. (Ying, W. 2008)

By comparing the function of other similar proteins, a hypothesis as to the function of DHRS1 can be made. 3-oxoacyl-(acyl-carrier-protein) reductase is also a member of the SDR protein family

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