CLCA: Maximum Common Molecular Substructure Queries within the MetRxn Database

Abstract

The challenge of automatically identifying the preserved molecular moieties in a chemical reaction is referred to as the atom mapping problem. Reaction atom maps provide the ability to locate the fate of individual atoms across an entire metabolic network. Atom maps are used to track atoms in isotope labeling experiments for metabolic flux elucidation, trace novel biosynthetic routes to a target compound, and contrast entire pathways for structural homology. However, rapid computation of the reaction atom mappings remains elusive despite significant research. We present a novel substructure search algorithm, canonical labeling for clique approximation (CLCA), with polynomial run-time complexity to quickly generate atom maps for all the reactions present in MetRxn. CLCA uses number theory (i.e., prime factorization) to generate canonical labels or unique IDs and identify a bijection between the vertices (atoms) of two distinct molecular graphs. CLCA utilizes molecular graphs generated by combining atomistic information on reactions and metabolites from 112 metabolic models and 8 metabolic databases. CLCA offers improvements in run time, accuracy, and memory utilization over existing heuristic and combinatorial maximum common substructure (MCS) search algorithms. We provide detailed examples on the various advantages as well as failure modes of CLCA over existing algorithms.

Comparative evaluation of atom mapping algorithms for balanced metabolic reactions: application to Recon 3D

“…However, this is somewhat lower than the reported accuracy [21, 22]. This discrepancy may be due to selection of a different set of manually curated atom mappings from the KEGG RPAIR database [2].…”

“…Six academic and commercially available atom mapping algorithms were included in our evaluation Reaction Decoder Tool (RDT, [10]), Determination of Reaction Mechanisms (DREAM, [11]), AutoMapper 5.0.1 (AutoMapper, [12], ChemAxon, Budapest, Hungary), Canonical Labeling for Clique Approximation (CLCA, [13]), Minimum Weighted Edit-Distance (MWED, [14]) within Pathway Tools, and InfoChem-Map (ICMAP, [15], InfoChem, Munich, Germany). These algorithms implement different prediction strategies or they use molecular properties, such as the bonds with hydrogen atoms or the use of the stereochemistry to predict atom mapping.…”

“…The Canonical Labelling for Clique Approximation [21] (CLCA) algorithm identifies the maximum common substructure between substrates and products using prime factorisation to generate canonical labels for bond-atoms. If a reaction has multiple reactant or product molecular graphs, many combinations of MCS exist.…”

Identification of Conserved Moieties in Metabolic Networks by Graph Theoretical Analysis of Atom Transition Networks

“…These reconstructions are accessible in a standardised format [18], e.g., through the BioModels database [24]. Atom mapping data are increasingly becoming accessible through biochemical databases but are still largely algorithmically generated [22,23]. KEGG [15,21] and BioPath (Molecular Networks GmbH, Erlangen, Germany) provide manually curated atom mappings but the data are not freely accessible.…”

Expanding Metabolic Capabilities Using Novel Pathway Designs: Computational Tools and Case Studies

“…While there are other retrosynthetic approaches based on similar rules derived from chemical features, the particular encoding of the molecular signature into chemical “moieties” enables its natural implementation within an optimization framework without information loss (e.g., stereoselectivity). For this task, the rePrime algorithm based on the canonical labeling for clique approximation (CLCA) algorithm was developed, which characterizes the loss and gain of molecular moieties around the reaction center. By enforcing global moiety balance for both, known and putative reactions in the candidate pathway, novoStoic can navigate uncharted chemical spaces by iteratively solving a MILP problem with minRxn or maximum profit as the objective.…”