Zhiwei Zhou

All Publications

• A widely distributed gene cluster compensates for uricase loss in hominids. Cell Liu, Y., Jarman, J. B., Low, Y. S., Augustijn, H. E., Huang, S., Chen, H., DeFeo, M. E., Sekiba, K., Hou, B. H., Meng, X., Weakley, A. M., Cabrera, A. V., Zhou, Z., van Wezel, G., Medema, M. H., Ganesan, C., Pao, A. C., Gombar, S., Dodd, D. 2023; 186 (16): 3400-3413.e20

  Abstract

  Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.

  View details for DOI 10.1016/j.cell.2023.06.010

  View details for PubMedID 37541197

• A mass spectrum-oriented computational method for ion mobility-resolved untargeted metabolomics NATURE COMMUNICATIONS Luo, M., Yin, Y., Zhou, Z., Zhang, H., Chen, X., Wang, H., Zhu, Z. 2023; 14 (1): 1813

  Abstract

  Ion mobility (IM) adds a new dimension to liquid chromatography-mass spectrometry-based untargeted metabolomics which significantly enhances coverage, sensitivity, and resolving power for analyzing the metabolome, particularly metabolite isomers. However, the high dimensionality of IM-resolved metabolomics data presents a great challenge to data processing, restricting its widespread applications. Here, we develop a mass spectrum-oriented bottom-up assembly algorithm for IM-resolved metabolomics that utilizes mass spectra to assemble four-dimensional peaks in a reverse order of multidimensional separation. We further develop the end-to-end computational framework Met4DX for peak detection, quantification and identification of metabolites in IM-resolved metabolomics. Benchmarking and validation of Met4DX demonstrates superior performance compared to existing tools with regard to coverage, sensitivity, peak fidelity and quantification precision. Importantly, Met4DX successfully detects and differentiates co-eluted metabolite isomers with small differences in the chromatographic and IM dimensions. Together, Met4DX advances metabolite discovery in biological organisms by deciphering the complex 4D metabolomics data.

  View details for DOI 10.1038/s41467-023-37539-0

  View details for Web of Science ID 000980769900015

  View details for PubMedID 37002244

  View details for PubMedCentralID PMC10066191

• Advanced analytical and informatic strategies for metabolite annotation in untargeted metabolomics TRAC-TRENDS IN ANALYTICAL CHEMISTRY Cai, Y., Zhou, Z., Zhu, Z. 2023; 158

  View details for DOI 10.1016/j.trac.2022.116903

  View details for Web of Science ID 000913934900001

• Metabolite annotation from knowns to unknowns through knowledge-guided multi-layer metabolic networking. Nature communications Zhou, Z., Luo, M., Zhang, H., Yin, Y., Cai, Y., Zhu, Z. 2022; 13 (1): 6656

  Abstract

  Liquid chromatography - mass spectrometry (LC-MS) based untargeted metabolomics allows to measure both known and unknown metabolites in the metabolome. However, unknown metabolite annotation is a major challenge in untargeted metabolomics. Here, we develop an approach, namely, knowledge-guided multi-layer network (KGMN), to enable global metabolite annotation from knowns to unknowns in untargeted metabolomics. The KGMN approach integrates three-layer networks, including knowledge-based metabolic reaction network, knowledge-guided MS/MS similarity network, and global peak correlation network. To demonstrate the principle, we apply KGMN in an invitro enzymatic reaction system and different biological samples, with ~100-300 putative unknowns annotated in each data set. Among them, >80% unknown metabolites are corroborated with insilico MS/MS tools. Finally, we validate 5 metabolites that are absent in common MS/MS libraries through repository mining and synthesis of chemical standards. Together, the KGMN approach enables efficient unknown annotations, and substantially advances the discovery of recurrent unknown metabolites for common biological samples from model organisms, towards deciphering dark matter in untargeted metabolomics.

  View details for DOI 10.1038/s41467-022-34537-6

  View details for PubMedID 36333358

• Global stable-isotope tracing metabolomics reveals system-wide metabolic alternations in aging Drosophila NATURE COMMUNICATIONS Wang, R., Yin, Y., Li, J., Wang, H., Lv, W., Gao, Y., Wang, T., Zhong, Y., Zhou, Z., Cai, Y., Su, X., Liu, N., Zhu, Z. 2022; 13 (1): 3518

  Abstract

  System-wide metabolic homeostasis is crucial for maintaining physiological functions of living organisms. Stable-isotope tracing metabolomics allows to unravel metabolic activity quantitatively by measuring the isotopically labeled metabolites, but has been largely restricted by coverage. Delineating system-wide metabolic homeostasis at the whole-organism level remains challenging. Here, we develop a global isotope tracing metabolomics technology to measure labeled metabolites with a metabolome-wide coverage. Using Drosophila as an aging model organism, we probe the in vivo tracing kinetics with quantitative information on labeling patterns, extents and rates on a metabolome-wide scale. We curate a system-wide metabolic network to characterize metabolic homeostasis and disclose a system-wide loss of metabolic coordinations that impacts both intra- and inter-tissue metabolic homeostasis significantly during Drosophila aging. Importantly, we reveal an unappreciated metabolic diversion from glycolysis to serine metabolism and purine metabolism as Drosophila aging. The developed technology facilitates a system-level understanding of metabolic regulation in living organisms.

  View details for DOI 10.1038/s41467-022-31268-6

  View details for Web of Science ID 000813768100022

  View details for PubMedID 35725845

  View details for PubMedCentralID PMC9209425

• Ion mobility collision cross-section atlas for known and unknown metabolite annotation in untargeted metabolomics NATURE COMMUNICATIONS Zhou, Z., Luo, M., Chen, X., Yin, Y., Xiong, X., Wang, R., Zhu, Z. 2020; 11 (1): 4334

  Abstract

  The metabolome includes not just known but also unknown metabolites; however, metabolite annotation remains the bottleneck in untargeted metabolomics. Ion mobility - mass spectrometry (IM-MS) has emerged as a promising technology by providing multi-dimensional characterizations of metabolites. Here, we curate an ion mobility CCS atlas, namely AllCCS, and develop an integrated strategy for metabolite annotation using known or unknown chemical structures. The AllCCS atlas covers vast chemical structures with >5000 experimental CCS records and ~12 million calculated CCS values for >1.6 million small molecules. We demonstrate the high accuracy and wide applicability of AllCCS with medium relative errors of 0.5-2% for a broad spectrum of small molecules. AllCCS combined with in silico MS/MS spectra facilitates multi-dimensional match and substantially improves the accuracy and coverage of both known and unknown metabolite annotation from biological samples. Together, AllCCS is a versatile resource that enables confident metabolite annotation, revealing comprehensive chemical and metabolic insights towards biological processes.

  View details for DOI 10.1038/s41467-020-18171-8

  View details for Web of Science ID 000607079100019

  View details for PubMedID 32859911

  View details for PubMedCentralID PMC7455731

• A lipidome atlas in MS-DIAL 4 NATURE BIOTECHNOLOGY Tsugawa, H., Ikeda, K., Takahashi, M., Satoh, A., Mori, Y., Uchino, H., Okahashi, N., Yamada, Y., Tada, I., Bonini, P., Higashi, Y., Okazaki, Y., Zhou, Z., Zhu, Z., Koelmel, J., Cajka, T., Fiehn, O., Saito, K., Arita, M., Arita, M. 2020; 38 (10): 1159-+

  Abstract

  We present Mass Spectrometry-Data Independent Analysis software version 4 (MS-DIAL 4), a comprehensive lipidome atlas with retention time, collision cross-section and tandem mass spectrometry information. We formulated mass spectral fragmentations of lipids across 117 lipid subclasses and included ion mobility tandem mass spectrometry. Using human, murine, algal and plant biological samples, we annotated and semiquantified 8,051 lipids using MS-DIAL 4 with a 1-2% estimated false discovery rate. MS-DIAL 4 helps standardize lipidomics data and discover lipid pathways.

  View details for DOI 10.1038/s41587-020-0531-2

  View details for Web of Science ID 000540408500002

  View details for PubMedID 32541957

  View details for PubMedCentralID 6660005

• The emerging role of ion mobility-mass spectrometry in lipidomics to facilitate lipid separation and identification TRAC-TRENDS IN ANALYTICAL CHEMISTRY Tu, J., Zhou, Z., Li, T., Zhu, Z. 2019; 116: 332-339

  View details for DOI 10.1016/j.trac.2019.03.017

  View details for Web of Science ID 000470827600031

• LipidIMMS Analyzer: integrating multi-dimensional information to support lipid identification in ion mobility-mass spectrometry based lipidomics BIOINFORMATICS Zhou, Z., Shen, X., Chen, X., Tu, J., Xiong, X., Zhu, Z. 2019; 35 (4): 698–700

  Abstract

  Ion mobility-mass spectrometry (IM-MS) has showed great application potential for lipidomics. However, IM-MS based lipidomics is significantly restricted by the available software for lipid structural identification. Here, we developed a software tool, namely, LipidIMMS Analyzer, to support the accurate identification of lipids in IM-MS. For the first time, the software incorporates a large-scale database covering over 260 000 lipids and four-dimensional structural information for each lipid [i.e. m/z, retention time (RT), collision cross-section (CCS) and MS/MS spectra]. Therefore, multi-dimensional information can be readily integrated to support lipid identifications, and significantly improve the coverage and confidence of identification. Currently, the software supports different IM-MS instruments and data acquisition approaches.The software is freely available at: http://imms.zhulab.cn/LipidIMMS/.Supplementary data are available at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/bty661

  View details for Web of Science ID 000459316300028

  View details for PubMedID 30052780

• Advancing the large-scale CCS database for metabolomics and lipidomics at the machine-learning era CURRENT OPINION IN CHEMICAL BIOLOGY Zhou, Z., Tu, J., Zhu, Z. 2018; 42: 34-41

  Abstract

  Metabolomics and lipidomics aim to comprehensively measure the dynamic changes of all metabolites and lipids that are present in biological systems. The use of ion mobility-mass spectrometry (IM-MS) for metabolomics and lipidomics has facilitated the separation and the identification of metabolites and lipids in complex biological samples. The collision cross-section (CCS) value derived from IM-MS is a valuable physiochemical property for the unambiguous identification of metabolites and lipids. However, CCS values obtained from experimental measurement and computational modeling are limited available, which significantly restricts the application of IM-MS. In this review, we will discuss the recently developed machine-learning based prediction approach, which could efficiently generate precise CCS databases in a large scale. We will also highlight the applications of CCS databases to support metabolomics and lipidomics.

  View details for DOI 10.1016/j.cbpa.2017.10.033

  View details for Web of Science ID 000427343000006

  View details for PubMedID 29136580

• LipidCCS: Prediction of Collision Cross-Section Values for Lipids with High Precision To Support Ion Mobility-Mass Spectrometry-Based Lipidomics ANALYTICAL CHEMISTRY Zhou, Z., Tu, J., Xiong, X., Shen, X., Zhu, Z. 2017; 89 (17): 9559–66

  Abstract

  The use of collision cross-section (CCS) values derived from ion mobility-mass spectrometry (IM-MS) has been proven to facilitate lipid identifications. Its utility is restricted by the limited availability of CCS values. Recently, the machine-learning algorithm-based prediction (e.g., MetCCS) is reported to generate CCS values in a large-scale. However, the prediction precision is not sufficient to differentiate lipids due to their high structural similarities and subtle differences on CCS values. To address this challenge, we developed a new approach, namely, LipidCCS, to precisely predict lipid CCS values. In LipidCCS, a set of molecular descriptors were optimized using bioinformatic approaches to comprehensively describe the subtle structure differences for lipids. The use of optimized molecular descriptors together with a large set of standard CCS values for lipids (458 in total) to build the prediction model significantly improved the precision. The prediction precision of LipidCCS was externally validated with median relative errors (MRE) of ∼1% using independent data sets across different instruments (Agilent DTIM-MS and Waters TWIM-MS) and laboratories. We also demonstrated that the improved precision in the predicted LipidCCS database (15 646 lipids and 63 434 CCS values in total) could effectively reduce false-positive identifications of lipids. Common users can freely access our LipidCCS web server for the following: (1) the prediction of lipid CCS values directly from SMILES structure; (2) database search; and (3) lipid match and identification. We believe LipidCCS will be a valuable tool to support IM-MS-based lipidomics. The web server is freely available on the Internet ( http://www.metabolomics-shanghai.org/LipidCCS/ ).

  View details for DOI 10.1021/acs.analchem.7b02625

  View details for Web of Science ID 000410014900133

  View details for PubMedID 28764323

• MetCCS predictor: a web server for predicting collision cross-section values of metabolites in ion mobility-mass spectrometry based metabolomics BIOINFORMATICS Zhou, Z., Xiong, X., Zhu, Z. 2017; 33 (14): 2235-2237

  Abstract

  In metabolomics, rigorous structural identification of metabolites presents a challenge for bioinformatics. The use of collision cross-section (CCS) values of metabolites derived from ion mobility-mass spectrometry effectively increases the confidence of metabolite identification, but this technique suffers from the limit number of available CCS values. Currently, there is no software available for rapidly generating the metabolites' CCS values. Here, we developed the first web server, namely, MetCCS Predictor, for predicting CCS values. It can predict the CCS values of metabolites using molecular descriptors within a few seconds. Common users with limited background on bioinformatics can benefit from this software and effectively improve the metabolite identification in metabolomics.The web server is freely available at: http://www.metabolomics-shanghai.org/MetCCS/ .jiangzhu@sioc.ac.cn.Supplementary data are available at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/btx140

  View details for Web of Science ID 000405289100080

  View details for PubMedID 28334295

• Large-Scale Prediction of Collision Cross-Section Values for Metabolites in Ion Mobility-Mass Spectrometry ANALYTICAL CHEMISTRY Zhou, Z., Shen, X., Tu, J., Zhu, Z. 2016; 88 (22): 11084–91

  Abstract

  The rapid development of metabolomics has significantly advanced health and disease related research. However, metabolite identification remains a major analytical challenge for untargeted metabolomics. While the use of collision cross-section (CCS) values obtained in ion mobility-mass spectrometry (IM-MS) effectively increases identification confidence of metabolites, it is restricted by the limited number of available CCS values for metabolites. Here, we demonstrated the use of a machine-learning algorithm called support vector regression (SVR) to develop a prediction method that utilized 14 common molecular descriptors to predict CCS values for metabolites. In this work, we first experimentally measured CCS values (ΩN2) of ∼400 metabolites in nitrogen buffer gas and used these values as training data to optimize the prediction method. The high prediction precision of this method was externally validated using an independent set of metabolites with a median relative error (MRE) of ∼3%, better than conventional theoretical calculation. Using the SVR based prediction method, a large-scale predicted CCS database was generated for 35 203 metabolites in the Human Metabolome Database (HMDB). For each metabolite, five different ion adducts in positive and negative modes were predicted, accounting for 176 015 CCS values in total. Finally, improved metabolite identification accuracy was demonstrated using real biological samples. Conclusively, our results proved that the SVR based prediction method can accurately predict nitrogen CCS values (ΩN2) of metabolites from molecular descriptors and effectively improve identification accuracy and efficiency in untargeted metabolomics. The predicted CCS database, namely, MetCCS, is freely available on the Internet.

  View details for DOI 10.1021/acs.analchem.6b03091

  View details for Web of Science ID 000388154700045

  View details for PubMedID 27768289