論文 - 詳細
| RRC ID | 51403 |
|---|---|
| 著者 | McReynolds MR, Wang W, Holleran LM, Hanna-Rose W. |
| タイトル | Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid. |
| ジャーナル | J Biol Chem |
| Abstract |
NAD+ biosynthesis is an attractive and promising therapeutic target for influencing health span and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD+ biosynthetic pathways. Here, we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD+ biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, Caenorhabditis elegans are reported to lack a de novo NAD+ biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of de novo NAD+ biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact de novo biosynthesis pathway for NAD+ from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD+ levels and partially reversed NAD+-dependent phenotypes caused by mutation of pnc-1, which encodes a nicotinamidase required for NAD+ salvage biosynthesis, demonstrating contribution of de novo synthesis to NAD+ homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosphoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD+ biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD+ biosynthesis creates novel possibilities for manipulating NAD+ biosynthetic pathways, which is key for the future of therapeutics. |
| 巻・号 | 292(27) |
| ページ | 11147-11153 |
| 公開日 | 2017-7-7 |
| DOI | 10.1074/jbc.C117.795344 |
| PII | S0021-9258(20)36989-1 |
| PMID | 28559281 |
| PMC | PMC5500784 |
| MeSH | Animals Caenorhabditis elegans* / enzymology Caenorhabditis elegans* / genetics Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Multienzyme Complexes* / genetics Multienzyme Complexes* / metabolism Mutation NAD* / biosynthesis NAD* / genetics Orotate Phosphoribosyltransferase* / genetics Orotate Phosphoribosyltransferase* / metabolism Orotidine-5'-Phosphate Decarboxylase* / genetics Orotidine-5'-Phosphate Decarboxylase* / metabolism Quinolinic Acid / metabolism* Tryptophan / genetics Tryptophan / metabolism |
| IF | 4.238 |
| 引用数 | 5 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 12 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm4924 tm6379 |