Shahreen Nabia, Chowdhury Niaz Bahar, Stone Edward, Knobbe Elle, Saha Rajib
Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln.
bioRxiv. 2024 Nov 19:2024.11.17.624049. doi: 10.1101/2024.11.17.624049.
, the causative agent of syphilis, poses a significant global health threat. Its strict intracellular lifestyle and challenges in cultivation have impeded detailed metabolic characterization. In this study, we present iTP251, the first genome-scale metabolic model of , reconstructed and extensively curated to capture its unique metabolic features. These refinements included the curation of key reactions such as pyrophosphate-dependent phosphorylation and pathways for nucleotide synthesis, amino acid synthesis, and cofactor metabolism. The model demonstrated high predictive accuracy, validated by a MEMOTE score of 92%. To further enhance its predictive capabilities, we developed ec-iTP251, an enzyme-constrained version of iTP251, incorporating enzyme turnover rate and molecular weight information for all reactions having gene-protein-reaction associations. Ec-iTP251 provides detailed insights into protein allocation across carbon sources, showing strong agreement with proteomics data (Pearson's correlation of 0.88) in the central carbon pathway. Moreover, the thermodynamic analysis revealed that lactate uptake serves as an additional ATP-generating strategy to utilize unused proteomes, albeit at the cost of reducing the driving force of the central carbon pathway by 27%. Subsequent analysis identified glycerol-3-phosphate dehydrogenase as an alternative electron sink, compensating for the absence of a conventional electron transport chain while maintaining cellular redox balance. These findings highlight 's metabolic adaptations for survival and redox balance in intracellular environments, providing a foundation for future research into its unique bioenergetics.
梅毒的病原体对全球健康构成重大威胁。其严格的细胞内生活方式以及培养方面的挑战阻碍了详细的代谢特征分析。在本研究中，我们提出了iTP251，这是首个梅毒的全基因组规模代谢模型，经过重建和广泛整理以捕捉其独特的代谢特征。这些改进包括对关键反应的整理，如焦磷酸依赖性磷酸化以及核苷酸合成、氨基酸合成和辅因子代谢途径。该模型显示出高预测准确性，通过MEMOTE评分为92%得到验证。为了进一步提高其预测能力，我们开发了ec-iTP251，它是iTP251的酶约束版本，纳入了所有具有基因-蛋白质-反应关联的反应的酶周转率和分子量信息。Ec-iTP251提供了关于跨碳源蛋白质分配的详细见解，在中心碳途径中与蛋白质组学数据显示出高度一致性（皮尔逊相关系数为0.88）。此外，热力学分析表明，乳酸摄取作为一种额外的ATP生成策略来利用未使用的蛋白质组，尽管这会使中心碳途径的驱动力降低27%。随后的分析确定3-磷酸甘油脱氢酶为替代电子受体，在维持细胞氧化还原平衡的同时补偿了传统电子传递链的缺失。这些发现突出了梅毒在细胞内环境中生存和氧化还原平衡的代谢适应性，为其独特生物能量学的未来研究奠定了基础。
