CDKAL1 (Cdk5 regulatory associated protein 1-like 1) is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1.[2] This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells.[3] CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.[4]
Structurally CDKAL1 is built of two iron (Fe) sulfur (S) clusters, therefore its function can be reduced by inhibiting Fe-S cluster biosynthesis[5]. Enzymatically, CDKAL1 catalyzes methylthiolation of N6-threonylcarbamoyl adenosine 37 (t6A37) in cytosolic tRNA, which has been determined to stabilize anticodon-codon interactions during translation.[6][7]
In humans, CDKAL1 is indicated to be involved in type II diabetes. CDKAL1 and TCF7L2 have been shown to reduce the production of insulin.[8] Some studies indicate that CDKAL1 variants modify tRNA resulting in increased risks of type II diabetes as well as obesity.[9] Variation in CDKAL1 was also attributed to differences in energy regulation. Single nucleotide polymorphism analysis resulted in the discovery of the mechanism of glucose and insulin responses demonstrated in the figure. From this relationship, it has been hypothesized that the regulatory genes CDKAL1 and GIP(glucose-dependent insulinotropic polypeptide) are related to environmental selectivity and adaptive immunity.[1]
In mice, CDKAL1 impairment reduces the mouse's ability to maintain glucose homeostasis and causes pancreatic islet hypertrophy, or pancreatic lesions.[10]
- ^ a b Chang, Chia Lin; Cai, James J.; Huang, Shang Yu; Cheng, Po Jen; Chueh, Ho Yen; Hsu, Sheau Yu Teddy (2014-09-15). "Adaptive Human CDKAL1 Variants Underlie Hormonal Response Variations at the Enteroinsular Axis". PLOS ONE. 9 (9): e105410. doi:10.1371/journal.pone.0105410. ISSN 1932-6203. PMC 4164438. PMID 25222615.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Ching, Yick-Pang; Pang, Andy S. H.; Lam, Wing-Ho; Qi, Robert Z.; Wang, Jerry H. (2002-05-03). "Identification of a Neuronal Cdk5 Activator-binding Protein as Cdk5 Inhibitor". Journal of Biological Chemistry. 277 (18): 15237–15240. doi:10.1074/jbc.C200032200. ISSN 0021-9258.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Wei, Fan-Yan; Nagashima, Kazuaki; Ohshima, Toshio; Saheki, Yasunori; Lu, Yun-Fei; Matsushita, Masayuki; Yamada, Yuichiro; Mikoshiba, Katsuhiko; Seino, Yutaka; Matsui, Hideki; Tomizawa, Kazuhito (2005-10). "Cdk5-dependent regulation of glucose-stimulated insulin secretion". Nature Medicine. 11 (10): 1104–1108. doi:10.1038/nm1299. ISSN 1078-8956.
{{cite journal}}: Check date values in:|date=(help) - ^ Takasugi, Toshiyuki; Minegishi, Seiji; Asada, Akiko; Saito, Taro; Kawahara, Hiroyuki; Hisanaga, Shin-ichi (2016-02-26). "Two Degradation Pathways of the p35 Cdk5 (Cyclin-dependent Kinase) Activation Subunit, Dependent and Independent of Ubiquitination". Journal of Biological Chemistry. 291 (9): 4649–4657. doi:10.1074/jbc.M115.692871. ISSN 0021-9258. PMC 4813488. PMID 26631721.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Santos, Maria C. Ferreira dos; Anderson, Cole P.; Neschen, Susanne; Zumbrennen-Bullough, Kimberly B.; Romney, Steven J.; Kahle-Stephan, Melanie; Rathkolb, Birgit; Gailus-Durner, Valerie; Fuchs, Helmut; Wolf, Eckhard; Rozman, Jan (2020-01-15). "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification". Nature Communications. 11 (1): 1–16. doi:10.1038/s41467-019-14004-5. ISSN 2041-1723. PMC 6962211. PMID 31941883.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Santos, Maria C. Ferreira dos; Anderson, Cole P.; Neschen, Susanne; Zumbrennen-Bullough, Kimberly B.; Romney, Steven J.; Kahle-Stephan, Melanie; Rathkolb, Birgit; Gailus-Durner, Valerie; Fuchs, Helmut; Wolf, Eckhard; Rozman, Jan (2020-01-15). "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification". Nature Communications. 11 (1): 1–16. doi:10.1038/s41467-019-14004-5. ISSN 2041-1723.
- ^ Harris, Kimberly A.; Bobay, Benjamin G.; Sarachan, Kathryn L.; Sims, Alexis F.; Bilbille, Yann; Deutsch, Christopher; Iwata-Reuyl, Dirk; Agris, Paul F. (2015-08-14). "NMR-based Structural Analysis of Threonylcarbamoyl-AMP Synthase and Its Substrate Interactions". Journal of Biological Chemistry. 290 (33): 20032–20043. doi:10.1074/jbc.M114.631242. ISSN 0021-9258. PMC 4536411. PMID 26060251.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Kirchhoff, K.; Machicao, F.; Haupt, A.; Schäfer, S. A.; Tschritter, O.; Staiger, H.; Stefan, N.; Häring, H.-U.; Fritsche, A. (2008-04-01). "Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion". Diabetologia. 51 (4): 597–601. doi:10.1007/s00125-008-0926-y. ISSN 1432-0428.
- ^ Palmer, Colin J.; Bruckner, Raphael J.; Paulo, Joao A.; Kazak, Lawrence; Long, Jonathan Z.; Mina, Amir I.; Deng, Zhaoming; LeClair, Katherine B.; Hall, Jessica A.; Hong, Shangyu; Zushin, Peter-James H. (2017-10). "Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue". Molecular Metabolism. 6 (10): 1212–1225. doi:10.1016/j.molmet.2017.07.013. PMC 5641635. PMID 29031721.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ Wei, Fan-Yan; Suzuki, Takeo; Watanabe, Sayaka; Kimura, Satoshi; Kaitsuka, Taku; Fujimura, Atsushi; Matsui, Hideki; Atta, Mohamed; Michiue, Hiroyuki; Fontecave, Marc; Yamagata, Kazuya (2011-09-01). "Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice". Journal of Clinical Investigation. 121 (9): 3598–3608. doi:10.1172/JCI58056. ISSN 0021-9738.