Clk-1

The clk-1 (Clock abnormal protein 1) gene encodes an enzyme (demethoxyubiquinone mono-oxygenase) that is necessary for ubiquinone biosynthesis in the worm C. elegans and other eukaryotes. The mouse version of the gene is called mclk1 and the human, fruit fly and yeast homolog COQ7. The clk-1 is not to be confused with the unrelated CLK1 human gene which plays a role in RNA splicing.

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Structure

The protein has two repeats of about 90 amino acids, that contain two conserved motifs. One of these DXEXXH may be part of an enzyme active site. The structure and function of the gene are highly conserved among different species (Liu, 2005).

The C.elegans protein contains 187 amino acid residues (20 kilodaltons), the human homolog 217 amino acid residues (24 kilodaltons, gene consisting of six exons spanning 11 kb and located on chromosome 16)(Asaumi et al, 1999; [1]).

Function

Ubiquinone is a small redox active lipid that is found in all membranes and that is a co-factor in numerous cellular redox processes, including mitochondrial electron transport. As a co-factor, ubiquinone is often involved in processes that produce reactive oxygen species (ROS). In addition, ubiquinone is one of the main endogenous antioxidants of the cell. The CLK-1 enzyme is responsible for the hydroxylation of 5-demethoxyubiquinone to 5-hydroxyubiquinone.

When ubiquinone biosyntesis is interrupted by the absence of the enzyme, cells accumulate an intermediate of ubiquinone biosynthesis, demethoxyubiquinone (DMQ).

It has been shown that mutations in the gene are associated with increased lifespan (Ewbank et al, 1997; Liu et al, 2005). Defects of the gene slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging (Felkai et al, 1999).

References

• Liu,X, Jiang,N, Hughes,B, Bigras,E, Shoubridge,E and Hekimi,S "Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice", Genes & Development, 19, 2005
• Asaumi S., Kuroyanagi H., Seki N., Shirasawa T, "Orthologues of the Caenorhabditis elegans longevity gene clk-1 in mouse and human.", Genomics 58, 1999
• Ewbank,J.J, Barnes,T.M, Lakowski,B, Lussier,M, Bussey,H, Hekimi,S, "Structural and Functional Conservation of the Caenorhabditis elegans Timing Gene clk-1", Science 14, 1997
• Felkai,S, Ewbank,J.J, Lemieux,J, Labbé,J.-C, Brown,G.G. and Hekimi,S "CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans", EMBO Journal 18, 1999