''CDKAL1'' (Cdk5 regulatory associated protein 1-like 1) is a gene in the

methylthiotransferase Methylthiotransferases are enzymes of the Radical SAM, radical S-adenosyl methionine (radical SAM) superfamily. These enzymes catalyze the addition of a methylthio group to various biochemical compounds including tRNA and proteins. Methylthiotransfe ...

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. This protein

CDK5 Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS). The molecule belongs t ...

regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells. CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.

Structure and function

Structurally CDKAL1 contains two iron (Fe) sulfur (S) clusters, therefore its function can be reduced by inhibiting Fe-S cluster biosynthesis. Enzymatically, CDKAL1 catalyzes methylthiolation of ''N''6-threonylcarbamoyl adenosine 37 (t6A37) in cytosolic tRNA, which has been determined to stabilize anticodon-codon interactions during translation.

Clinical significance

In humans, CDKAL1 is indicated to be involved in

type II diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

. Mutations in ''CDKAL1'' and ''

TCF7L2 Transcription factor 7-like 2 (T-cell specific, HMG-box), also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the ''TCF7L2'' gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, co ...

'' have been associated with low production of insulin. Some studies indicate that CDKAL1 variants modify tRNA resulting in increased risks of

as well as

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. Variation in CDKAL1 was also attributed to differences in energy regulation.

Single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

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 Gastric inhibitory polypeptide (GIP), also known as glucose-dependent insulinotropic polypeptide, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incre ...

) are related to environmental selectivity and adaptive immunity. CDKAL_and_GIP_Variant_Schematic

Genome-wide association studies have linked

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

s in an

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

on chromosome 6 with susceptibility to

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

`. rovided by RefSeq, May 2010

Animal studies

In mice, CDKAL1 impairment reduces the mouse's ability to maintain glucose homeostasis and causes pancreatic islet hypertrophy, or pancreatic lesions.

Structure and function

Clinical significance

Animal studies

References

External links

Further reading