Recombinant Human Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1)

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Cat. No.
BT2454087
Source
in vitro E.coli expression system
Synonyms
CDKAL1; Threonylcarbamoyladenosine tRNA methylthiotransferase; CDK5 regulatory subunit-associated protein 1-like 1; tRNA-t(6A37 methylthiotransferase
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Description

Definition and Classification

Recombinant Human CDKAL1 is a methylthiotransferase enzyme responsible for post-transcriptional modification of tRNA molecules. Specifically, it catalyzes the conversion of N<sup>6</sup>-threonylcarbamoyladenosine (t<sup>6</sup>A) to 2-methylthio-N<sup>6</sup>-threonylcarbamoyladenosine (ms<sup>2</sup>t<sup>6</sup>A) at position 37 (A<sup>37</sup>) of cytosolic tRNA<sup>Lys</sup> (tRNA Lys3) . This modification enhances translational fidelity by stabilizing codon-anticodon interactions during ribosomal decoding .

Mechanism of Action

CDKAL1 modifies tRNA<sup>Lys</sup> to ensure accurate translation of lysine codons (AAA/AAG) in mRNA, particularly critical for proinsulin synthesis in pancreatic β-cells :

  1. tRNA Modification: Adds a methylthio group to t<sup>6</sup>A<sup>37</sup>, enhancing anticodon stability and ribosome decoding fidelity .

  2. Proinsulin Processing: Prevents misincorporation of amino acids, ensuring proper folding and secretion of mature insulin .

  3. ER Stress Mitigation: Deficiency in CDKAL1 leads to ER stress (elevated CHOP10) and impaired insulin granule protein translation .

Type 2 Diabetes (T2D)

CDKAL1 is a T2D susceptibility gene identified in genome-wide association studies (GWAS) . Key findings:

  • Genetic Risk: SNPs in intron 5 of CDKAL1 increase T2D risk (odds ratio ~1.15) .

  • Mechanistic Links:

    • β-Cell Dysfunction: Reduced CDKAL1 activity impairs first-phase insulin exocytosis due to defective mitochondrial ATP production and K<sub>ATP</sub> channel responsiveness .

    • Proinsulin Misfolding: Inefficient tRNA modification leads to ER stress and degradation of proinsulin .

StudyKey FindingsImplication
Ohara-Imaizumi et al. (2010)CDKAL1 KO mice show reduced mitochondrial ATP, impaired K<sub>ATP</sub> channel activityFirst-phase insulin secretion defects
Brambillasca et al. (2012)CDKAL1 downregulation elevates ER stress markers (CHOP10) in β-cellsβ-Cell failure in T2D
Wei et al. (2011)CDKAL1 rescues tRNA Lys modification in yqeV bacterial mutantsEvolutionary conservation of function

Adipocyte Differentiation

CDKAL1 suppresses adipogenesis via Wnt/β-catenin signaling, independent of its enzymatic activity :

  • Mechanism: Overexpression of CDKAL1 increases active β-catenin and GSK-3β phosphorylation (Ser9), inhibiting PPARγ and lipid accumulation .

  • Functional Impact: Mutations in Fe-S clusters (CS1/CS2) abrogate anti-adipogenic effects, highlighting structural requirements for signaling regulation .

In Vitro Studies

  1. tRNA Modification Assays:

    • CDKAL1 knockdown in NIT-1 cells reduces ms<sup>2</sup>t<sup>6</sup>A levels, impairing insulin secretion .

    • Enzyme activity depends on Fe-S clusters; mutations (e.g., CS12) abolish tRNA modification .

  2. Adipocyte Models:

    • CDKAL1 overexpression in 3T3-L1 cells reduces lipid accumulation and PPARγ expression by 60–80% .

In Vivo Models

  1. Pancreatic β-Cells:

    • Cdkal1 KO mice exhibit defective first-phase insulin release and glucose intolerance .

  2. Adipose Tissue:

    • CDKAL1 knockdown promotes adipogenesis, linking it to obesity-related metabolic disorders .

Therapeutic and Diagnostic Potential

  • T2D Treatment: Targeting CDKAL1 to enhance β-cell function or mitigate ER stress is under investigation .

  • Biomarker: Polymorphisms in CDKAL1 (e.g., rs7754840) are used in T2D risk stratification .

Product Specs

Form
Lyophilized powder
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Lead Time
Delivery times vary depending on the purchase method and location. Consult your local distributor for precise delivery estimates.
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Notes
Avoid repeated freeze-thaw cycles. Store working aliquots at 4°C for up to one week.
Reconstitution
Centrifuge the vial briefly before opening to consolidate the contents. Reconstitute the protein in sterile, deionized water to a concentration of 0.1-1.0 mg/mL. For long-term storage, we recommend adding 5-50% glycerol (final concentration) and aliquoting at -20°C/-80°C. Our standard glycerol concentration is 50%, provided as a reference for customer use.
Shelf Life
Shelf life depends on various factors, including storage conditions, buffer composition, temperature, and protein stability. Generally, liquid formulations have a 6-month shelf life at -20°C/-80°C, while lyophilized forms have a 12-month shelf life at -20°C/-80°C.
Storage Condition
Upon receipt, store at -20°C/-80°C. Aliquoting is essential for multiple uses. Avoid repeated freeze-thaw cycles.
Tag Info
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Synonyms
CDKAL1; Threonylcarbamoyladenosine tRNA methylthiotransferase; CDK5 regulatory subunit-associated protein 1-like 1; tRNA-t(6A37 methylthiotransferase
Buffer Before Lyophilization
Tris/PBS-based buffer, 6% Trehalose.
Datasheet
Please contact us to get it.
Expression Region
1-579
Protein Length
full length protein
Species
Homo sapiens (Human)
Target Names
CDKAL1
Target Protein Sequence
MPSASCDTLLDDIEDIVSQEDSKPQDRHFVRKDVVPKVRRRNTQKYLQEEENSPPSDSTI PGIQKIWIRTWGCSHNNSDGEYMAGQLAAYGYKITENASDADLWLLNSCTVKNPAEDHFR NSIKKAQEENKKIVLAGCVPQAQPRQDYLKGLSIIGVQQIDRVVEVVEETIKGHSVRLLG QKKDNGRRLGGARLDLPKIRKNPLIEIISINTGCLNACTYCKTKHARGNLASYPIDELVD RAKQSFQEGVCEIWLTSEDTGAYGRDIGTNLPTLLWKLVEVIPEGAMLRLGMTNPPYILE HLEEMAKILNHPRVYAFLHIPVQSASDSVLMEMKREYCVADFKRVVDFLKEKVPGITIAT DIICGFPGETDQDFQETVKLVEEYKFPSLFINQFYPRPGTPAAKMEQVPAQVKKQRTKDL SRVFHSYSPYDHKIGERQQVLVTEESFDSKFYVAHNQFYEQVLVPKNPAFMGKMVEVDIY ESGKHFMKGQPVSDAKVYTPSISKPLAKGEVSGLTKDFRNGLGNQLSSGSHTSAASQCDS ASSRMVLPMPRLHQDCALRMSVGLALLGLLFAFFVKVYN
Uniprot No.
Q5VV42

Target Background

Function
This protein catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t⁶A), resulting in the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms²t⁶A) at position 37 in tRNAs that recognize codons beginning with adenine.
Gene References Into Functions
  1. A non-significant association was observed between two single nucleotide polymorphisms (SNPs) in CDKAL1 (rs7754840) and CDKN2A/2B (rs10811661) and gestational diabetes mellitus (GDM). PMID: 29544538
  2. The chromosomal region 6p22.3 has been identified as a novel susceptibility locus for nonsyndromic cleft lip/palate (nsCL/P). The location of risk variants within the CDKAL1 intronic sequence, containing enhancer elements predicted to regulate SOX4 transcription, suggests SOX4 as a potential candidate gene for this craniofacial anomaly, rather than CDKAL1 itself. PMID: 29403086
  3. Further CDKAL1 variants are needed to validate the association between CDKAL1 and gestational glycemic traits. PMID: 28502787
  4. Forced MT1E expression mitigated both the hypersensitivity of CDKAL1 mutant cells to glycolipotoxicity and pancreatic beta-cell dysfunction in vitro and in vivo. PMID: 28538172
  5. The CDKAL1 gene is associated with type 2 diabetes development, while this association is absent for the HHEX/IDE locus. PMID: 29372795
  6. A family-based GWAS of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence Alzheimer's Disease risk (rs7609954 in PTPRG, rs1347297 in OSBPL6, and rs1513625 near PDCL3). Additionally, rs72953347 in OSBPL6 and two SNPs in CDKAL1 showed marginally significant associations with late-onset Alzheimer's Disease (LOAD) (rs10456232, P-value=4.76 x 10⁻⁷; rs62400067, P-value=3.54 x 10⁻⁷). PMID: 26830138
  7. Multivariate logistic regression analysis of CDKAL1 SNPs showed significant associations, highlighting the gene's role in T2DM pathophysiology. All three analyzed SNPs in CDKAL1 and CDKN2A/B genes were significantly associated with T2DM, unlike the two SNPs in HHEX. PMID: 27377502
  8. This study showed prospective associations between JMJD1C and KCNQ1 SNPs and type 2 diabetes (T2D) risk in a Korean population. CDKAL1 may not be associated with T2D onset after age 40. PMID: 28406950
  9. This research suggests an association between rs6908425 in CDKAL1 and the risk of developing SAPHO syndrome in Han Chinese populations, with the risk allele T potentially increasing susceptibility. PMID: 27936930
  10. This study investigated the association between eight SNPs in three genetic loci (CDKAL1, CDKN2A/2B, and FTO) and type 2 diabetes (T2D) in a Uyghur population. PMID: 26873362
  11. Findings suggest that CDKAL1 gene variants significantly affect the response to anti-TNF therapies in psoriasis patients. PMID: 26563541
  12. Risk alleles for six loci (ADCY5, ADRA2A, CDKAL1, CDKN2A/B, GRB10, and TCF7L2) increased glucose levels from birth to age 5. PMID: 27049325
  13. rs10946398 was associated with markers of impaired insulin secretion. PMID: 26119585
  14. Novel selection signals were observed in CDKAL1 and NEGR1, known diabetes and obesity susceptibility genes. PMID: 25370040
  15. SNP rs7754840 in CDKAL1, rs864745 in JAZF1, and rs35767 in IGF1 may be susceptibility loci for type 2 diabetes in the Uyghur population. PMID: 25785549
  16. The rs7754840 and rs7756992 SNPs in the CDKAL1 gene were associated with gestational diabetes mellitus in a South Indian population. PMID: 25723968
  17. An association was identified between type 2 diabetes risk variants in CDKAL1 and birth weight in Chinese Han individuals, with risk allele carriers exhibiting a trend towards reduced birth weight. PMID: 26168825
  18. This study provides evidence against a role for dysregulated CDKAL1-v1 expression in mediating the association between intronic SNPs in CDKAL1 and type 2 diabetes susceptibility. PMID: 25634229
  19. The results support a central role for CDKAL1 and TCF7L2 in T2DM susceptibility in Southwest Asian populations, offering insight into the disease's molecular mechanisms. PMID: 25483131
  20. The CDKAL1 gene rs7756992 A/G polymorphism was significantly associated with T2DM, suggesting that individuals with the G allele may be predisposed. PMID: 24185407
  21. rs7756992 of the CDKAL1 gene showed a protective effect against diabetic nephropathy. PMID: 24636221
  22. Variants in CDKAL1 were associated with glucose-induced GIP and insulin response. PMID: 25222615
  23. Meta-analysis indicated significant associations between the IGF2BP2 rs4402960 and CDKAL1 rs7756992 polymorphisms and increased diabetes risk in Arab populations. PMID: 24898818
  24. CDKAL1-v1-mediated suppression of CDKAL1 may be involved in the pathogenesis of type 2 diabetes in individuals carrying risk SNPs. PMID: 24760768
  25. This study reports an association between CDKAL1-related SNPs and insulin resistance, a clinical marker for type 2 diabetes, in a cohort of Greek children and adolescents. PMID: 24695378
  26. These data indicate the potential importance of CDKAL1 protein and HHEX homeobox protein in glucose homeostasis in an Alaska Native population with low type 2 diabetes (T2D) prevalence. PMID: 24112421
  27. Five of fourteen loci contained SNPs identified in European studies, while the remaining nine were distinct. Conditional analysis identified seven secondary signals and an independent novel locus at the 3' end of CDKAL1. PMID: 24013783
  28. This study substantiates the roles of CAMK1D and CDKAL1 in gluconeogenic and glyconeogenic pathways in primary human hepatocytes. PMID: 23840313
  29. Meta-analysis showed significant associations between CDKN2A/B gene rs10811661 and CDKAL1 gene rs7756992 and rs10946398 and type 2 diabetes. PMID: 24012816
  30. TCF7L2 was replicated (P = 0.004; combined analysis P = 3.8 x 10⁻⁶), and type 2 diabetes SNPs near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with childhood-onset familial type 2 diabetes (CFRD). PMID: 23670970
  31. CDKAL1 may influence compensatory mechanisms regulating glucose homeostasis through dietary interactions. PMID: 23173044
  32. CDKAL1 is a tail-anchored protein in the endoplasmic reticulum (ER) of insulinoma cells. PMID: 23048041
  33. rs7754840 (CDKAL1) was associated with non-obese type 2 diabetes, and rs7903146 (TCF7L2) with early-onset type 2 diabetes. PMID: 22923468
  34. None of the twelve SNPs in six genes (KCNJ11, TCF7L2, SLC30A8, HHEX, FTO, and CDKAL1) identified in GWAS were associated with polycystic ovary syndrome. PMID: 22443257
  35. Genetic variants of CDKAL1 and VEGFA on chromosome 6 may contribute to T2D risk in the Chinese population. PMID: 22437209
  36. This study examined associations between SNPs of TCF7L2, CDKAL1, SLC30A8, and HHEX and the development of diabetic retinopathy (DR) and diabetic nephropathy (DN). PMID: 22487833
  37. CDKAL1 may influence glycosylated hemoglobin levels. PMID: 22290723
  38. A significant association was found between type 2 diabetes mellitus, increased fasting plasma glucose, and rs7754840 in CDKAL1 in lean Han Chinese. PMID: 21643948
  39. CDKAL1 rs7754840 and rs7756992, but not CDKN2A/2B rs10811661, were associated with T2DM in the Lebanese population. PMID: 22119613
  40. Common variants in CDKAL1 and KLF9 were associated with body mass index in East Asian populations. PMID: 22344221
  41. Six SNPs (rs7754840 in CDKAL1, rs391300 in SRR, rs2383208 in CDKN2A/2B, rs4402960 in IGF2BP2, rs10830963 in MTNR1B, rs4607517 in GCK) associated with type 2 diabetes risk were also associated with gestational diabetes mellitus (GDM) in pregnant Chinese women. PMID: 22096510
  42. Variants in the CDKAL1 gene have been consistently associated with reduced first-phase insulin secretion and type 2 diabetes development. PMID: 21908934
  43. CDKAL1 is involved in T2D pathogenesis through impaired beta-cell function. PMID: 21611789
  44. SNP analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with type 2 diabetes mellitus susceptibility in females but not males. PMID: 21368910
  45. No association was found between single nucleotide polymorphisms in CDKAL1 and polycystic ovary syndrome or related clinical features in Chinese women. PMID: 19718565
  46. No relationship was observed between CDKAL1 and KCNQ1 polymorphisms and earlier onset of type 2 diabetes. PMID: 21416855
  47. An interaction between CDKAL1 polymorphism and dietary energy intake influences the dysglycemic phenotype leading to metabolic syndrome (MetS), possibly through impaired insulin secretion. The CDKAL1 polymorphism may serve as a MetS marker in the Japanese population. PMID: 20847106
  48. Meta-analysis indicated significant associations between CDKAL1 polymorphisms and type 2 diabetes. PMID: 20568056
  49. This study reports a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birth weight, and confirms in meta-analyses associations between decreased birth weight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. PMID: 20490451
  50. Significant associations were identified between variants in CDKN2A/B, CDKAL1, and TCF7L2 and type 2 diabetes in a Han Chinese cohort, suggesting these genes as strong candidates for conferring susceptibility across ethnicities. PMID: 20161779
Database Links

HGNC: 21050

OMIM: 125853

KEGG: hsa:54901

STRING: 9606.ENSP00000274695

UniGene: Hs.657604

Involvement In Disease
Diabetes mellitus, non-insulin-dependent (NIDDM)
Protein Families
Methylthiotransferase family, CDKAL1 subfamily
Subcellular Location
Endoplasmic reticulum membrane; Single-pass membrane protein.
Tissue Specificity
Expressed in pancreatic islets.

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