Review
Gene to ScreenOrphan enzymes could be an unexplored reservoir of new drug targets
Gene to Screen
Section snippets
Defining enzyme activities and their putative sensitivity to drugs
Enzymatic processes have been analyzed in various organisms, by biochemists. These studies span a wide catalogue of data that have been gathered over several decades – from the mere description of a newly detected activity to studies that disclose many features of an enzyme in thorough detail. As early as the 1960s, an international effort was launched to organize all the pieces of information and to check its validity and consistency. Accordingly, the International Enzyme Commission (EC)
Introducing the concept of orphan enzymes
The EC classification of enzyme activities is constantly evolving because the curators of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology are deciding on the best definition for each enzymatic activity (in relation to their specific expertise). Note that, an EC number denotes an enzyme activity but not the enzyme itself that catalyzes this activity. Thus, different sequences and structures can share the same EC number (see later).
Currently (September
Are orphan enzymes currently used as drug targets?
In a recent review, Robertson [9] listed 71 EC numbers for enzymes that are targets for marketed drugs. These enzyme activities are present in humans (48), bacteria (13), viruses (5), fungi (4) and protists (1).
Unexpectedly, we found that there were orphans even among enzymes used as drug targets. Three of the 71 reported activities inhibited by drugs have no associated sequences. Here is the detailed list of these orphan EC numbers used as targets for pharmaceutical drugs:
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The vitamin-K-epoxide
Looking for orphan enzymes in metabolic pathways that could be used as new drug targets
A recent review [13] proposed the comparison of the metabolic pathways in protozoan parasites with those of their human hosts, to facilitate the identification of new drug targets against major diseases such as malaria, leishmaniasis, Chagas disease and trypanosomiasis. Indeed, human cells synthesize only ten amino acids (Y, A, S, G, E, Q, P, D, N and C) and many of the pathways involved are absent in protozoan parasites. To cope with these auxotrophies, the parasites developed alternative
Looking for orphan enzymes, from nonmetabolic pathways, that could be used as new drug targets
Table 3 describes a large panel of orphan EC numbers representing enzymes, involved in cell metabolism, with the potential to be putative drug targets. However, the relative proportion of EC numbers without sequence goes from 27.3% (among the enzymes involved in metabolism) to 52.1% (in the case of nonmetabolic enzymes). It might be interesting to look at these nonmetabolic enzymes despite the fact that they represent less than one-third of the total population of defined enzymes. A few
The difficulties in targeting orphan enzymes
One might wonder why there are still so many orphan enzymes, especially because the genomes of many species have been completely sequenced. As well as the difficulty that is inherent to annotation problems, we would like to emphasize other points that complicate the process of targeting enzyme macromolecules to specific therapeutic drugs. Some of these hindrances are conceptual; others are relevant to applied research.
First, it is very important to understand that an EC number represents an
Conclusions
Most diseases are of a complex nature and, over the years, it became more and more evident that reductionist approaches were insufficient tools to deliver a complete understanding. Previous reductionist approaches have suffered from drawbacks, such as focusing on the putative drug target without completely understanding its role in the pathophysiology of the disease. As we previously stated, this was evident in the case of moonlighting proteins 31, 32, 33. Recent studies have shown that
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Cited by (10)
Optimization of protease production and sequence analysis of the purified enzyme from the cold adapted yeast Rhodotorula mucilaginosa CBMAI 1528
2020, Biotechnology ReportsCitation Excerpt :The molecular weight was estimated to be approximately 30 kDa, and the isoelectric point 4.5. The enzyme was named as Rhodotorulapepsin (EC 3.4.23.26); however, until now, the enzyme has not had an associated sequence and has been classified as an orphan enzyme as it had a EC number without an associated sequence [38]. Based on the results collected here, we can reasonably propose that the aspartic protease described in the present study may be the Rodothorulapepsin described years ago.
Leveraging structure for enzyme function prediction: Methods, opportunities, and challenges
2014, Trends in Biochemical SciencesCitation Excerpt :The original publication dates for orphan ECs ranges from the 1950s to today, with a mean of 1977 [72,73]. Many orphan ECs have biologically important roles, and could be an unexplored reservoir of new drug targets [72,80]. Our incomplete understanding of metabolism is also reflected by ‘dead-end’ metabolites.
Systems biology: Constraint-based reconstruction and analysis
2015, Systems Biology: Constraint-Based Reconstruction and AnalysisProfiling the orphan enzymes
2014, Biology DirectA detailed genome-wide reconstruction of mouse metabolism based on human Recon 1
2010, BMC Systems BiologySystematizing the generation of missing metabolic knowledge
2010, Biotechnology and Bioengineering