Tracing metabolic pathways from enzyme data

Abstract

The IUBMB Enzyme List is widely used by other databases as a source for avoiding ambiguity in the recognition of enzymes as catalytic entities. However, it was never designed for activities such as pathway tracing, which have become increasingly important in systems biology. This is because it often relies on generic or representative reactions to show the reactions catalysed by enzymes of wide specificity. It is necessary to go to databases such as BRENDA to find further, more detailed, information on what is known about the range of substrates for any particular enzyme. In order to provide a framework for tracing pathways involving any specific enzyme or metabolite, we have created a Reactions Database from the material in the Enzyme List. This allows reactions to be searched by substrate/product and pathways to be traced from any selected starting/seed substrate. An extensive synonym glossary allows searches by many of the alternative names, including accepted abbreviations, by which a chemical compound may be known. This database was necessary for the development of the application Reaction Explorer (http://www.reaction-explorer.org), which was written in REALbasic to search the Reactions Database and draw metabolic pathways from reactions selected by the user. Having input the name of the starting compound (the "seed"), the user is presented with a list of all reactions containing that compound and then selects the product of interest as the next point on the ensuing graph. The pathway diagram is then generated as the process iterates. A contextual menu is provided, which allows the user to (i) remove a compound from the graph, along with all associated links; (ii) search the reactions database again for additional reactions involving the compound and (iii) search for the compound within the Enzyme List.

Fifty‐five years of enzyme classification: advances and difficulties

“…Although the number of alternative reactions catalysed by some enzymes is being expanded, the Enzyme List does not aim to be exhaustive in this respect. It is possible to trace some metabolic pathways by use of the enzyme list , but the fact that not all substrates for an enzyme are listed is a limiting factor. However, there are many other reaction or reactant databases that may be used to fill any gaps, such as BRENDA , the R‐Pair system in KEGG REACTION , MetaCyc , Rhea , and UM‐BBD .…”

Enzyme nomenclature and classification: the state of the art

“…Synthetic catalysts and enzymes that have been chemically or genetically modified to alter their activities or specificities are not included, although bacterial enzymes that are induced through growth on artificial substrates are. This offers the potential for using the Enzyme List for metabolic pathway construction, which would be undermined by inclusion of artificial enzymes, although the design and purpose of the system limit such an application [24,25]. It follows that the substrates should, whenever possible, also be compounds that an enzyme might encounter physiologically.…”

Parameter Reliability and Understanding Enzyme Function

“…A more difficult problem has been that many investigators who have been interested in the kinetic behaviour of specific enzymes have used assay conditions that are favourable to their studies without regard for the physiological conditions under which the enzyme may operate in the tissues [ 17 ]. For example, many studies on the behaviour of alcohol dehydrogenase have involved alkaline pH values (e.g., [ 18 ]), simply because the reaction equilibrium favours aldehyde oxidation at neutral pH values [ 19 ], which have generally been used for studies in the reverse direction. It is, of course, unhelpful in studies of reversible reactions for different pH values to have been used for the forward and reverse directions, which would, for example, make it impractical to determine the equilibrium constant from Haldane relationships [ 1 , 5 ].…”