KARS Human
Description
Molecular Function and Evolutionary Conservation
KARS ensures tRNA<sup>Lys</sup> charging via a two-step reaction:
The enzyme’s dual localization (cytoplasm and mitochondria) makes it indispensable for cellular metabolism. Evolutionary analyses reveal high conservation of key residues (e.g., Leu133, Tyr173, Ile302) across species, suggesting functional indispensability .
Genetic Variants and Associated Disorders
Pathogenic KARS variants are linked to:
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Charcot-Marie-Tooth (CMT) disease: Compound heterozygosity (e.g., p.Leu133His and p.Tyr173SerfsX7) disrupts enzyme activity, impairing axon function .
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Autosomal-recessive nonsyndromic hearing loss (ARNSHI): Homozygous variants (e.g., p.Tyr173His, p.Asp377Asn) affect cochlear structures .
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Neurodevelopmental disorders: Biallelic variants correlate with intellectual disability and developmental delays .
Table 1: Clinically Relevant KARS Variants
Table 2: Enzymatic Activity of KARS Variants1
| Variant | (μM) | (s) | Relative Activity |
|---|---|---|---|
| Wild-type | 1.8 ± 0.9 | 1.4 ± 0.1 | 1.0 |
| p.Leu133His | 5.8 ± 2.4 | 0.3 ± 0.3 | 0.06 |
| p.Ile302Met | 2.1 ± 0.8 | 2.7 ± 1.6 | 1.6 |
| p.Thr623Ser | 3.5 ± 0.1 | 4.0 ± 0.7 | 1.4 |
The p.Leu133His variant disrupts dimer-dimer interactions critical for tRNA binding, while p.Tyr173SerfsX7 truncates the catalytic domain, abolishing function .
Mechanistic Insights from Model Organisms
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Zebrafish: kars knockdown causes hearing loss and neurodevelopmental deficits, mirroring human phenotypes .
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Yeast: Human disease-associated variants (e.g., p.Leu133His) phenocopy yeast KRS1 mutations, validating functional conservation .
Clinical Implications and Unresolved Questions
Product Specs
Product Science Overview
Lysyl-tRNA synthetase (LysRS) is an essential enzyme in the process of protein synthesis. It belongs to the family of aminoacyl-tRNA synthetases (aaRSs), which are responsible for attaching amino acids to their corresponding tRNAs, a process known as tRNA aminoacylation or tRNA charging. This enzyme specifically catalyzes the attachment of lysine to its cognate tRNA, forming lysyl-tRNA, which is then used in the ribosome for protein synthesis.
Human LysRS is a component of the multi-tRNA synthetase complex (MSC), which includes several other aaRSs and non-enzyme proteins. The MSC is crucial not only for protein translation but also for various cellular pathways such as immune response and cell migration . The structure of LysRS is dynamic and can be stabilized by forming complexes with other proteins, such as aminoacyl-tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This interaction helps maintain the enzyme’s activity under stressed conditions .
The evolutionary emergence of the MSC in metazoans, including humans, is believed to protect the aminoacyl-tRNA synthetase components from being modified or recruited for other cellular pathways . This complex formation is less common in single-celled organisms, where LysRS and other aaRSs typically function independently.
LysRS has been implicated in various diseases, including cancer. For instance, the enzyme’s activity is significantly upregulated in hepatocellular carcinoma (HCC) tumor tissues compared to tumor-free liver tissues . This upregulation is associated with worse patient survival and higher tumor recurrence, making LysRS a potential therapeutic target in liver cancer .
