Abstract
Thousands of biochemical reactions with characterized biochemical activities are still orphan. Novel reactions predicted by pathway generation tools also lack associated protein sequences and genes. Mapping orphan and novel reactions back to the known biochemistry and proposing genes for their catalytic functions is a daunting problem. We propose a new method, BridgIT, to identify candidate genes and protein sequences for orphan and novel enzymatic reactions. BridgIT introduces, for the first time, the information of the enzyme binding pocket into reaction similarity comparisons. It ascertains the similarity of two reactions by comparing the reactive sites of their substrates and their surrounding structures, along with the structures of the generated products. BridgIT compares orphan and novel reactions to enzymatic reactions with known protein sequences, and then, it proposes protein sequences and genes of the most similar non-orphan reactions as candidates for catalyzing the novel or orphan reactions. We performed BridgIT analysis of orphan reactions from KEGG 2011 (Kyoto Encyclopedia of Genes and Genomes, published in 2011) that became non-orphan in KEGG 2016, and BridgIT correctly predicted enzymes with identical third- and fourth-level EC numbers for 91% and 56% of these reactions, respectively. BridgIT results revealed that it is sufficient to know information about six atoms together with their connecting bonds around the reactive sites of the substrates to match a protein sequence to the catalytic activity of enzymatic reactions with maximal accuracy. Moreover, the same information about only three atoms around the reactive site allowed us to correctly match 87% of the analyzed enzymatic reactions. Finally, we used BridgIT to provide candidate protein sequences for 137,000 novel enzymatic reactions from the recently introduced ATLAS of Biochemistry. A web-tool of BridgIT can be consulted at http://lcsb-databases.epfl.ch/BridgIT/.
