Kinase Subfamily KACAD

Kinase Classification: Group PKL: Family CAK: Subfamily KACAD

KACAD is a CAK kinase fused to an ACAD (acyl-coA dehydrogenase) in many eukaryotes, and also found in some bacteria. KACADs were first described in profile searches for remote homologs of kinases [1, 2]

Evolution

KACAD is found in in most eukaryotes and some bacteria, mostly proteobacteria and actinomycetes. Distinct ACAD10 and ACAD11 members are seen in most animal genomes

Domain Structure

Human ACAD11 has a CAK kinase domain on the N-terminus and an ACAD (sometimes represented as one domain, sometimes as 3) on the C-terminus. ACAD10 adds a HAD (haloacid dehydrogenase) domain on the further N-terminus. The HAD domain is only found in animal members. All KACADs appear to be catalytically active, based on the presence of key catalytic motifs.

Functions

ACADs participate in beta-oxidation of fatty acids. ACAD10 and ACAD11 have been characterized in just one paper [3], which shows that they use very long fatty acids as substrates and have selective and different expression patterns in human brain. Another study [4] associated ACAD10 SNPs with diabetes and lowered lipid oxidation, while expression of ACAD11 and other lipid metabolizing enzymes was elevated in in mouse liver after manipulation of the gut microbiome. ACAD10 is transcriptionally upregulated in response to the diabetes drug metformin in both human and C. elegans, and this is required for metformins growth inhibitory effect in worms and human cancer cell lines [5]. A lncRNA that targets ACAD10 may also be involved in regulation of brown and white adipose tissue [6]

A plant KACAD, IBR3, is involved in response to auxin signaling [7], in a beta-oxidation-like process.

References

1. Kannan N, Taylor SS, Zhai Y, Venter JC, and Manning G. Structural and functional diversity of the microbial kinome. PLoS Biol. 2007 Mar;5(3):e17. DOI:10.1371/journal.pbio.0050017 |
2. Briedis KM, Starr A, and Bourne PE. Analysis of the human kinome using methods including fold recognition reveals two novel kinases. PLoS One. 2008 Feb 13;3(2):e1597. DOI:10.1371/journal.pone.0001597 |
3. He M, Pei Z, Mohsen AW, Watkins P, Murdoch G, Van Veldhoven PP, Ensenauer R, and Vockley J. Identification and characterization of new long chain acyl-CoA dehydrogenases. Mol Genet Metab. 2011 Apr;102(4):418-29. DOI:10.1016/j.ymgme.2010.12.005 |
4. Bian L, Hanson RL, Muller YL, Ma L, MAGIC Investigators, Kobes S, Knowler WC, Bogardus C, and Baier LJ. Variants in ACAD10 are associated with type 2 diabetes, insulin resistance and lipid oxidation in Pima Indians. Diabetologia. 2010 Jul;53(7):1349-53. DOI:10.1007/s00125-010-1695-y |
5. Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, Gygi SP, Zheng B, and Soukas AA. An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. Cell. 2016 Dec 15;167(7):1705-1718.e13. DOI:10.1016/j.cell.2016.11.055 |
6. Chen J, Cui X, Shi C, Chen L, Yang L, Pang L, Zhang J, Guo X, Wang J, and Ji C. Differential lncRNA expression profiles in brown and white adipose tissues. Mol Genet Genomics. 2015 Apr;290(2):699-707. DOI:10.1007/s00438-014-0954-x |
7. Zolman BK, Nyberg M, and Bartel B. IBR3, a novel peroxisomal acyl-CoA dehydrogenase-like protein required for indole-3-butyric acid response. Plant Mol Biol. 2007 May;64(1-2):59-72. DOI:10.1007/s11103-007-9134-2 |