{"title":"含黄素单加氧酶3 (FMO3)变体催化功能(未受影响或受损)的计算机二元分类及其在日本基因组资源数据库中发现的新变体的体外验证","authors":"Makiko Shimizu, Eiji Hishinuma, Rika Igarashi, Sakae Saito, Miaki Makiguchi, Masahiro Hiratsuka, Hiroshi Yamazaki","doi":"10.1248/bpb.b25-00359","DOIUrl":null,"url":null,"abstract":"<p><p>Functionally impaired human flavin-containing monooxygenase 3 (FMO3) variants are associated with metabolic trimethylaminuria. The present study predicted the level of impairment of catalytic function of eight FMO3 variants newly detected in the updated Tohoku Medical Megabank. Catalytic function was modeled using the in vitro intrinsic trimethylamine N-oxygenation activities of 108 FMO3 variants using a logistic linear regression model. FMO3 proteins with single, double, triple, and quadruple amino acid variants underwent binary classification as unaffected (score 0) or impaired (≤70% of wild-type FMO3, score 1) based on their trimethylamine N-oxygenation activities. Using a model with the sum of the coefficients before and after amino acid substitutions, the mean probabilities of 62 FMO3 variants with impaired catalytic activities (0.78) were significantly higher than those of 46 with unaffected catalytic activities (0.30) (p < 0.01). The area under the corresponding receiver operating characteristic curve was 0.91. This in silico evaluation was applied to eight FMO3 variants (p.Met82Thr, p.Gly180Val, p.Ile212Leu, p.Asn275Ile, p.Gly276Glu, p.Ala377Asp, p.Tyr469Cys, and p.Val502Gly) newly found in the Tohoku Medical Megabank and validated in vitro. The present model could prove useful for estimating the activities of new FMO3 variants by applying a logistic linear regression model based on in vitro-generated catalytic data.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 7","pages":"1062-1069"},"PeriodicalIF":1.7000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In Silico Binary Classification of Catalytic Function (Unaffected or Impaired) of Flavin-Containing Monooxygenase 3 (FMO3) Variants and in Vitro Validation Using New Variants Found in a Japanese Genome Resource Database.\",\"authors\":\"Makiko Shimizu, Eiji Hishinuma, Rika Igarashi, Sakae Saito, Miaki Makiguchi, Masahiro Hiratsuka, Hiroshi Yamazaki\",\"doi\":\"10.1248/bpb.b25-00359\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Functionally impaired human flavin-containing monooxygenase 3 (FMO3) variants are associated with metabolic trimethylaminuria. 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This in silico evaluation was applied to eight FMO3 variants (p.Met82Thr, p.Gly180Val, p.Ile212Leu, p.Asn275Ile, p.Gly276Glu, p.Ala377Asp, p.Tyr469Cys, and p.Val502Gly) newly found in the Tohoku Medical Megabank and validated in vitro. 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引用次数: 0
摘要
功能受损的人类含黄素单加氧酶3 (FMO3)变异与代谢性三甲胺尿有关。本研究预测了更新后的Tohoku Medical Megabank中新发现的8种FMO3变异的催化功能损伤水平。采用logistic线性回归模型对108个FMO3突变体体外三甲胺n -氧合活性进行建模。单、双、三、四种氨基酸变异的FMO3蛋白根据其三甲胺n -氧合活性分为未受影响(0分)和受损(≤70%的野生型FMO3, 1分)。利用氨基酸取代前后的系数和模型,62个FMO3突变体催化活性受损的平均概率(0.78)显著高于46个催化活性未受影响的平均概率(0.30)(p < 0.01)。相应的受试者工作特征曲线下面积为0.91。该计算机评估应用于Tohoku Medical Megabank中新发现的8个FMO3变异(p.Met82Thr、p.Gly180Val、p.Ile212Leu、p.Asn275Ile、p.Gly276Glu、p.Ala377Asp、p.Tyr469Cys和p.Val502Gly),并进行了体外验证。基于体外生成的催化数据,该模型可以应用逻辑线性回归模型来估计新的FMO3变体的活性。
In Silico Binary Classification of Catalytic Function (Unaffected or Impaired) of Flavin-Containing Monooxygenase 3 (FMO3) Variants and in Vitro Validation Using New Variants Found in a Japanese Genome Resource Database.
Functionally impaired human flavin-containing monooxygenase 3 (FMO3) variants are associated with metabolic trimethylaminuria. The present study predicted the level of impairment of catalytic function of eight FMO3 variants newly detected in the updated Tohoku Medical Megabank. Catalytic function was modeled using the in vitro intrinsic trimethylamine N-oxygenation activities of 108 FMO3 variants using a logistic linear regression model. FMO3 proteins with single, double, triple, and quadruple amino acid variants underwent binary classification as unaffected (score 0) or impaired (≤70% of wild-type FMO3, score 1) based on their trimethylamine N-oxygenation activities. Using a model with the sum of the coefficients before and after amino acid substitutions, the mean probabilities of 62 FMO3 variants with impaired catalytic activities (0.78) were significantly higher than those of 46 with unaffected catalytic activities (0.30) (p < 0.01). The area under the corresponding receiver operating characteristic curve was 0.91. This in silico evaluation was applied to eight FMO3 variants (p.Met82Thr, p.Gly180Val, p.Ile212Leu, p.Asn275Ile, p.Gly276Glu, p.Ala377Asp, p.Tyr469Cys, and p.Val502Gly) newly found in the Tohoku Medical Megabank and validated in vitro. The present model could prove useful for estimating the activities of new FMO3 variants by applying a logistic linear regression model based on in vitro-generated catalytic data.
期刊介绍:
Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012.
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