CoMAP: A Program to Cluster Pathways Overrepresented with Specific Cofactors in Human, Mouse, and Yeast Biology

Background: Protein cofactors, such as metal ions are an essential part of many proteins, playing key structural, regulatory, and enzymatic roles. Without these cofactors, roughly one-third of all proteins would cease functioning properly. Deficiencies of these cofactors can have detrimental effects on health, contributing to the development of various diseases. The same is true for mice and yeast. It is evident then that the concentrations of cofactors must be carefully maintained so as not to damage the organism. The Cofactor Mapping & Analysis Program (CoMAP), allows users to determine the pathways in human, mouse, and yeast biology where any cofactor crucial to protein function is significantly involved. This tool enables the identification of biological processes and specific pathways within an organism that are influenced by changes in cofactor concentrations, providing a deeper insight into cofactor-dependent proteins and their involvement in biology. Results: To our knowledge, no other bioinformatics tool exists with the same functionality as CoMAP. Via a graphical user interface CoMAP constructs a list of the Ensembl gene IDs encoding for proteins containing specific cofactor(s), performs an overrepresentation analysis to identify the significant pathways in the organism using these genes, and hierarchically clusters these pathways based on similarities in their gene sets. A use case, investigating ferroptosis in humans, was done using this method. The example application took in iron II, iron III, and later, iron-sulfur clusters as the selected cofactors, identifying the pathways in human biology that would be affected by ferroptosis. The program returned pathways that have been experimentally shown to be impacted by ferroptosis in addition to novel pathways. The CoMAP Python script is available at https://github.com/tcraddock/CoMAP. Conclusions: CoMAP provides insight into the cellular functions most likely to be affected by a depletion or augmentation of the cofactor(s). CoMAP has use cases, applications and future directions for the fields of bioengineering of biological pathways, advancing personalized medicine, and elucidating to new ways to treat diseases resulting from cofactor deficiency and/or imbalance.