Tuobang Lia,b,c,1a- Technion-Israel Institute of Technology, Haifa 32000, Israel; b- Guangdong Technion-Israel Institute of Technology, Shantou 515063, China;c- University of California, Berkeley, CA 94720Metabolic pathways are fundamental maps in biochemistry that detail how molecules are transformed through various reactions. Metabolomics refers to the large-scale study of small molecules. High-throughput, untargeted, mass spectrometry-based metabolomics experiments typically depend on libraries for structural annotation, which is necessary for pathway analysis. However, only a small fraction of spectra can be matched to known structures in these libraries and only a portion of annotated metabolites can be associated with specific pathways, considering that numerous pathways are yet to be discovered. The complexity of metabolic pathways, where a single compound can play a part in multiple pathways, poses an additional challenge. This study introduces a different concept: mass-weighted intensity distribution, which is the empirical distribution of the intensities times their associated m/z values. Analysis of COVID-19 and mouse brain datasets shows that by estimating the differences of the point estimations of these distributions, it becomes possible to infer the metabolic directions and magnitudes without requiring knowledge of the exact chemical structures of these compounds and their related pathways. The overall metabolic momentum map, named as momentome, has the potential to bypass the current bottleneck and provide fresh insights into metabolomics studies. This brief report thus provides a mathematical framing for a classic biological concept.
| is the magnitude of this change, which can be further stan2 ( Sn,A + Sn,B). Combing this dardized by dividing it by 1 magnitude with the direction, it is called a metabolic momentum of sample A and B of n molecules of interest with regards to scale. Analogously, higher-order standardized moments of the mass spectra distribution of sample A of n molecules of kSM n,A. However, their biologiinterest, can be denoted as cal signicance is much weaker. For example, Pearson mode skewness is based on the dierence between the mean and mode. In a metabolomics dataset, most compounds are trace amounts, meaning the mode should always be close to zero. Therefore, if the skewness increases, the location estimates should also increase in most cases. Similar logic can be deduced for the relation of kurtosis and scale. Due to the ex-
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In this brief report, Hodges-Lehmann estimator (H-L) (21) and median standard deviation (msd) (22) are used as the location and scale estimators. The overall picture of metabolic momentums of dierent classes is named as momentome (Table 2). Results Here, two metabolomics studies are used as examples.
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For both CA and CO, purine-related metabolism signicantly towards anabolism and duobolism compared to the healthy volunteers (Table 2), aligned with a previous study that showed purine metabolism is signicantly up-regulated after SARS-CoV-2 infection (24). Acylcarnitine-related pathways exhibit a signicant inclination towards catabolism and centrabolism (Table 2). This conclusion, which does not require knowledge of individual compounds within the acylcarnitine class, was also emphasized by Yang et al. (23). It was observed that long-chain acylcarnitines were generally lower in both convalescent groups, while medium-chain acylcarnitines displayed the opposite pattern (23). Bile acid-related pathways leaned towards anabolism and duobolism in CA group, while bile acids have been reported to be immunomodulatory (25, 26).
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Organooxygen compounds-related pathways leaned towards catabolism in both convalescent groups. The only accurately annotated compound in this class is kynurenine. This aligns with a previous study that found the kynurenine pathway, which is the primary catabolic pathway of tryptophan, is signicantly up-regulated in COVID-19 patients (27, 28). For both CA and CO, metabolism related to carbohydrates signicantly shifts towards anabolism and duabolism compared to that of healthy volunteers (Table 2). This might be due to the dysregulated glucose metabolism (29, 30). Because the massweighted intensity distribution is the product of the concentration of the molecules and their mass, if the mass shrinks to half during a reaction but the concentration doubles, the location of the mass-weighted intensity distribution should generally remain the same. In addition, many intermediates in the glycolytic pathway have higher molecular weights than glucose, e.g., glucose-6-phosphate. Therefore,
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