Identification of Eukaryotic and Prokaryotic Methylthiotransferase for Biosynthesis of 2-Methylthio-N6-threonylcarbamoyladenosine in tRNA

Arragain, Simon; Handelman, Samuel K.; Forouhar, F.; Wei, Fan Yan; Tomizawa, Kazuhito; Hunt, J.F.; Douki, Thierry; Fontecave, Marc; Mulliez, Etienne; Atta, Mohamed

doi:10.1074/jbc.m110.106831

Cited by 111 publications

(110 citation statements)

References 30 publications

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“…In amino acid sequence, Cdkal1 is highly similar to MiaB and YqeV, which are bacterial MTTase proteins [21]. Both MiaB and YqeV are involved in the methylthiolational modifications of tRNA from bacteria to mammals.…”

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

“…MiaB catalyzes the methylthiolation of N 6 -isopentenyladenosine (i 6 A) to generate 2-methylthio-N 6 -isopentenyladenosine (ms 2 i 6 A) at position 37 (A 37 ), 3'-adjacent to the anticodon in some tRNAs [22,29]. In contrast, YqeV catalyzes the methylthiolation of N 6 -threonyl carbamoyladenosine (t 6 A) to synthesize 2-methylthio-N 6 -threonyl carbamoyladenosine (ms 2 t 6 A) for tRNA in bacteria [21]. Cdkal1 is a mammalian methylthiotransferase that biosynthe- …”

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

“…However, Cdkal1 has no ability to interact with Cdk5 activators and no effect on Cdk5 activity [19,20]. The primary structure of Cdkal1 has features of the methylthiotransferase (MTTase) family, a subclass of the large radical AdoMet enzyme superfamily [21]. The MTTase family catalyzes chemically challenging reactions, in all cases involving a C-H to C-SCH 3 bound conversion, through a radical mechanism [21].…”

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

“…The primary structure of Cdkal1 has features of the methylthiotransferase (MTTase) family, a subclass of the large radical AdoMet enzyme superfamily [21]. The MTTase family catalyzes chemically challenging reactions, in all cases involving a C-H to C-SCH 3 bound conversion, through a radical mechanism [21]. These reactions participate in important biological processes such as tRNA or ribosomal protein modification [22][23][24][25].…”

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

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Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

Wei

Tomizawa

2011

Endocr J

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Abstract.A number of whole-genome association studies show the cdk5 regulatory associated protein 1-like 1 (cdkal1) gene to be one of the most reproducible risk genes in type 2 diabetes (T2D). Variations in the gene are associated with impaired insulin secretion but not insulin resistance or obesity. Although the physiological functions of Cdkal1 had been unclear, recent studies show that it is a tRNA modification enzyme, a mammalian methylthiotransferase that biosynthesizes 2-methylthio- A modification in tRNA Lys (UUU) is important for preventing the misreading of its cognate codons, especially when the rate of translation is relatively high. In both general and pancreatic β-cell-specific cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed. Moreover, the β-cell-specific knockout mice show pancreatic islet hypertrophy and impaired blood glucose control. The mice are also hypersensitive to high-fat diet-induced endoplasmic reticulum (ER) stress. In this review, we provide an overview of the physiological functions of Cdkal1 and the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

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Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

Section: Physiological Functions Of Cdkal1mentioning

confidence: 99%

See 2 more Smart Citations

Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

Wei

Tomizawa

2011

Endocr J

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“…Individuals carrying the risk allele of CDKAL1 have decreased insulin secretion (7 ). We recently reported that CDKAL1 is a tRNA-modifying enzyme that catalyzes 2-methylthio (ms 2 ) transformation of (9 ). The ms 2 modification is required for accurate decoding of the lysine codon (4 ).…”

confidence: 99%

Quantitative PCR Measurement of tRNA 2-Methylthio Modification for Assessing Type 2 Diabetes Risk

et al. 2013

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BACKGROUND Genetic variants in the human CDKAL1 (CDK5 regulatory subunit associated protein 1–like 1) gene have been associated with reduced insulin secretion and type 2 diabetes (T2D). CDKAL1 is a methylthiotransferase that catalyzes 2-methylthio (ms2) modification of the adenine at position 37 (A37) of cytoplasmic tRNALys(UUU). We investigated the ms2-modification level of tRNALys(UUU) as a direct readout of CDKAL1 enzyme activity in human samples. METHOD We developed a quantitative PCR (qPCR)-based method to measure ms2 modification. tRNALys(UUU) was reverse-transcribed with 2 unique primers: Reverse primer r1 was designed to anneal to the middle of this tRNA, including the nucleotide at A37, and reverse primer r2 was designed to anneal to the region downstream (3′) of A37. Subsequent qPCR was performed to detect the corresponding transcribed cDNAs. RESULTS The efficiency of reverse transcription of tRNALys(UUU) was ms2-modification dependent. The relative difference in threshold cycle number obtained with the r1 or r2 primer yielded the ms2-modification level in tRNALys(UUU) precisely as predicted by an original mathematical model. The method was capable of measuring ms2-modification levels in tRNALys(UUU) in total RNA isolated from human peripheral blood samples, revealing that the ms2-modification rate in tRNALys(UUU) was decreased in individuals carrying the CDKAL1 genotype associated with T2D. In addition, the ms2-modification level was correlated with insulin secretion. CONCLUSIONS The results point to the critical role of ms2 modification in T2D and to a potential clinical use of a simple and high-throughput method for assessing T2D risk.

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Mitochondrial alterations in the cochlea of Cdk5rap1‐knockout mice with age‐related hearing loss

Miwa

Katsuno²,

Wei

et al. 2023

FEBS Open Bio

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Previous studies have revealed that age‐related hearing loss (AHL) in Cdk5 regulatory subunit‐associated protein 1 (Cdk5rap1)‐knockout mice is associated with pathology in the cochlea. Here, we aimed to identify mitochondrial alterations in the cochlea of Cdk5rap1‐knockout mice with AHL. Mitochondria in the spiral ganglion neurons (SGNs) and hair cells (HCs) were normal despite senescence; however, the mitochondria of types I, II, and IV spiral ligament fibrocytes were ballooned, damaged, and ballooned, respectively, in the stria vascularis. Our results suggest that the accumulation of dysfunctional mitochondria in the lateral wall, rather than the loss of HCs and SGNs, leads to the onset of AHL. Our results provide valuable information regarding the underlying mechanisms of AHL and the relationship between aberrant tRNA modification‐induced hearing loss and mitochondrial dysfunction.

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Identification of Eukaryotic and Prokaryotic Methylthiotransferase for Biosynthesis of 2-Methylthio-N6-threonylcarbamoyladenosine in tRNA

Cited by 111 publications

References 30 publications

Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

Quantitative PCR Measurement of tRNA 2-Methylthio Modification for Assessing Type 2 Diabetes Risk

Mitochondrial alterations in the cochlea of Cdk5rap1‐knockout mice with age‐related hearing loss

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