Simultaneous prediction of enzyme orthologs from chemical transformation patterns for de novo metabolic pathway reconstruction

Abstract

Motivation: Metabolic pathways are an important class of molecular networks consisting of compounds, enzymes and their interactions. The understanding of global metabolic pathways is extremely important for various applications in ecology and pharmacology. However, large parts of metabolic pathways remain unknown, and most organism-specific pathways contain many missing enzymes. Results: In this study we propose a novel method to predict the enzyme orthologs that catalyze the putative reactions to facilitate the de novo reconstruction of metabolic pathways from metabolome-scale compound sets. The algorithm detects the chemical transformation patterns of substrate–product pairs using chemical graph alignments, and constructs a set of enzyme-specific classifiers to simultaneously predict all the enzyme orthologs that could catalyze the putative reactions of the substrate–product pairs in the joint learning framework. The originality of the method lies in its ability to make predictions for thousands of enzyme orthologs simultaneously, as well as its extraction of enzyme-specific chemical transformation patterns of substrate–product pairs. We demonstrate the usefulness of the proposed method by applying it to some ten thousands of metabolic compounds, and analyze the extracted chemical transformation patterns that provide insights into the characteristics and specificities of enzymes. The proposed method will open the door to both primary (central) and secondary metabolism in genomics research, increasing research productivity to tackle a wide variety of environmental and public health matters.Availability and Implementation:Contact: maskot@bio.titech.ac.jp

Leveraging Heterogeneous Network Embedding for Metabolic Pathway Prediction

“…Despite the potential benefits of adopting ML methods for pathway prediction from genomic sequence information, Pathologic remains the primary inference engine of Pathway Tools ( [21]), and alternative methods for pathway-centric inference expanding on the generic methods described above remain nascent. Several of these methods incorporate metabolite information to improve pathway inference and reaction rules to infer metabolic pathways ( [7,33,32]). Other methods including BiomeNet ( [29]) and MetaNetSim ( [19]) dispense with pathways all together and model reaction networks based on enzyme abundance information.…”

Integrating bioinformatics approaches for a comprehensive interpretation of metabolomics datasets

“…Pathway prediction algorithms map substrate/product pairs to enzymatic activities and then to genes [45,46]. Metabolism enumeration algorithms can be used to find novel reactions that are not yet catalogued in biochemical databases [47].…”

SimCAL: a flexible tool to compute biochemical reaction similarity

“…Knowledge of biochemical reaction similarity is important for a wide range of biotechnological applications, such as, classification of enzymes [ 1 – 4 ], identification of missing enzymes in metabolic pathways [ 5 , 6 ], identification of promiscuous enzymes in understanding the metabolic network evolution [ 7 ] and mine specific reaction substrates and the inhibitors [ 8 – 11 ]. Similarity between chemical reactions, referred to as reaction similarity, can be calculated at multiple levels: Transformation level similarity is computed by considering only the atoms and bonds that are undergoing transformation, at different degrees of neighborhood information [ 12 ].…”