A survey of orphan enzyme activities

Abstract

Background: Using computational database searches, we have demonstrated previously that no gene sequences could be found for at least 36% of enzyme activities that have been assigned an Enzyme Commission number. Here we present a follow-up literature-based survey involving a statistically significant sample of such "orphan" activities. The survey was intended to determine whether sequences for these enzyme activities are truly unknown, or whether these sequences are absent from the public sequence databases but can be found in the literature.

Results: We demonstrate that for ~80% of sampled orphans, the absence of sequence data is bona fide. Our analyses further substantiate the notion that many of these enzyme activities play biologically important roles.

Conclusion: This survey points toward significant scientific cost of having such a large fraction of characterized enzyme activities disconnected from sequence data. It also suggests that a larger effort, beginning with a comprehensive survey of all putative orphan activities, would resolve nearly 300 artifactual orphans and reconnect a wealth of enzyme research with modern genomics. For these reasons, we propose that a systematic effort to identify the cognate genes of orphan enzymes be undertaken.

Figure 1

Example of a metabolic pathway involving a validated orphan.

Figure 2

Literature survey process.

Figure 3

Distribution of enzymatic activities in validated orphans. The percentage of validated orphan activities belonging to each EC class is shown.

Figure 4

Publication year of original publications describing orphan activities. The publication date associated with the original source articles of all instances of orphans surveyed here is plotted (286 instances of orphans, corresponding to 228 activities), based upon the IUBMB record. In a number of cases more than one instance of an orphan activity was evaluated because the activity was reported in more than one species.

Figure 5

Salvageability ranking of validated orphans. The suitability of validated orphans for eventual cloning of at least one cognate gene was evaluated according to the ranking system described in the text. Out of 228 orphans, 57 were judged to be salvageable. A: Overall salvageability ranking (percentage out of 57); B: Domain distribution of salvageable orphans (number of orphans). Note that the total is greater than 57 because some orphans have different evaluations in the different species in which they have been reported. One orphan is also shared between Eubacteria and Eukaryotes.

Figure 6

Distribution of enzymatic activities for salvageable orphans ranked "good" and "excellent".