*This webpage was produced as an assignment for an undergraduate course at Davidson college. *
Glucokinase Orthologs
Glucokinase is responsible for the first step in the glycolytic pathway (Devlin, 1982). This is one essential step in the metabolism of glucose, a food source for a number of different organisms. Therefore one would believe that this protein would be conserved in organisms using glucose as a food source. Kamata et al. (2004) state that the glucose binding site of the protein is made up of six important amino acids. These amino acids are Threonine in the 168 position, lysine in the 169 position, aspargine in the 204 position, aspartic acid in the 205 position, and finally glutamic acid in the 256 and 290 positions (Kamata et al., 2004). It was determined that there were many orthologs for glucokinase through BLAST and Ensembl analysis, however I will only choose a select few of the 702 hits to discuss.
Brown Rat (Rattus norvegicus)
The brown rat is another member of the mammal family and contains the protein glucokinase. This protein is 465 amino acids in length and is highly conserved from human glucokinase being 87.38% the same in DNA sequence and 94.84% conserved in the amino acid sequence. The sequence is also conserved in the noted amino acids responsible for glucose binding; therefore its function is predicted to be similar if not identical in the brown rat. The complete amino acid sequence for human glucokinase and brown rat.
House mouse (Mus musculus)
The House mouse another model organism for genomic research also contains an ortholog to the human glucokinase protein. The glucokinase protein in the mouse also contains 465 amino acids. This protein is the most highly conserved of the orthologs to glucokinase having 89.1% the same in DNA sequence and 95.91 % conserved in amino acid sequence. The complete amino acid sequence for human glucokinase and house mouse.
Dog (Canis familiaris)
The dog also contains an ortholog to the human glucokinase protein. However this protein is truncated and only contains 284 amino acids, about 200 less than the human version. With this truncation the final amino acids needed for glucose binding are also missing, causing one to wonder if the function of the protein is affected by this truncation. The 284 amino acids that remain are highly conserved leading one to believe that it may be possible the protein can still function. The complete amino acid sequence for human glucokinase and dog.
Yeast (Saccharomyces cerevisiae)
Common baker's yeast is one of several organisms used in much of the genomic research and its genomic code has been deciphered. Yeast contains a glucokinase protein which is 485 amino acids in length and is 44 % conserved from DNA sequence and 33 % conserved in the amino acids from the human glucokinase (Genecards). Even though it is not highly conserved The necessary amino acids for the formation of the glucose binding site are left intact and are highly conserved. However one portion known to mutate in humans is not present in the yeast glucokinase. The complete amino acid sequence for human glucokinase and yeast.
The Pipid Frog (Xenopus tropicalis)
The pipid frog is the only member of its family suitable for use in genetic studies because it is the only diploid member (http://faculty.virginia.edu/xtropicalis/). There has been much research done on ths unique frog and it has been determined that a form of glucokinase closely resembling that of humans. The form of glucokinase has 450 amino acids and is highly conserved between the two species. The glucose binding site is also conserved allowing the protein to function in the same way. The complete amino acid sequence for human glucokinase and pipid frog.
Green spotted pufferfish (Tetraodon nigroviridis)
The green spotted puffer fish is another fish that has a conserved human glucokinase ortholog. This ortholog contains 488 amino acids and has conserved glucose binding sites, suggesting that the function of glucokinase is similar in both fish and humans. The complete amino acid sequence for human glucokinase and green spotted pufferfish.
Japanese Pufferfish (Fubu rubripes)
The Japanese puffer fish contains a glucokinase ortholog that is 477 amino acids, and is highly conserved between humans and the Japanese puffer fish. The six amino acids required to bind glucose are completely conserved. The complete amino acid sequence for human glucokinase and Japanese pufferfish.
The amino acid sequences for C. elegans and Drosophila melanogaster were found but the orthologs found in these species were not as highly conserved as the above mentioned orthologs. C. elegans has multiple orthologs, with the most highly conserved having a 45% conserved amino acid sequence. D. melanogaster is similar having a 47% conserved amino acid sequence.
Table of orthologs can be found at GeneCards.
Disease associated with glucokinase mutations:
Glucokinase plays an important role in diabetes, because it plays a role in glucose up take in the pancreas and liver which are defective in patients with type II diabetes. There have been studies to determine what the most common mutation of glucokinase is and if it is sufficient to cause the onset of diabetes. Missense mutations in glucokinase have been linked to the onset of type two diabetes. A mutation in amino acid 299 from glycine to arginine has been found to cause this early onset (Stoffel et al., 1992) It has also been found that a mutation in amino acid number 261 from glycine to arginine will also cause the onset of type II diabetes (Eto et al., 1993) One drug company has targeted glucokinase and has found a way to turn this molecule "on" or make it active, providing a way to treat diabetes (Unknown, 2003). However i could not locate any information on where this drug binding site is located in the glucokinase protein. .
References:
Devlin, Thomas. Ed. Textbook of Biochemistry: with clinical correlations. New York: Wiley Medical Publication. 1982.
Eto K, Sakura H, Shimokawa K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Kadowaki T. 1993 August.Sequence variations of the glucokinase gene in Japanese subjects with NIDDM - non-insulin-dependent diabetes mellitus. Diabetes. <http://www.findarticles.com/p/articles/mi_m0922/is_n8_v42/ai_14105709>
Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y. 2004 March. Structural Basis for allosteric Regulation of the monomeric allosteric enzyme human Glucokinase. Structure 12(3):429-38.
Stoffel M, Patel P, Lo Y, Hattersley A, Lucassen A, Page R, Bell J, Bell G, Turner R, Wainscoat J. 1992 October. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nat. Genetics 2(2):153-6
Unknown. Protein Holds Promise as New Diabetes Drug Target: Chemical activates glucokinase enzyme and could improve insulin secretion. July 17, 2003. <http://diabetes.about.com/library/blnews/blnrochedrug703.htm> Last accessed on Feb. 15, 2005.
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Any questions or concerns regarding this page should be directed to Matt Gemberling.