Background on orphan enzymes

Solving the orphan enzyme problem

What is an orphan enzyme?

An orphan enzyme is an enzyme activity for which we have experimental data (the reaction it catalyzes, at a minimum) but no amino acid or nucleotide sequence data. You can read the “What is an orphan enzyme?” page for more information.

What’s the difference between an orphan and a species-specific orphan?

An “orphan enzyme” is an enzyme that has no sequence information of any kind in any species. Sometimes researchers refer to an enzyme as an “orphan” because it lacks sequence information in a specific species. We refer to these as “species-specific” or “local” orphan enzymes. Local orphans can often be resolved through the use of sequence data from enzymes catalyzing the same reaction in other species.

For example, if an enzyme has a known sequence in several species but none in human, we might refer to it as a local orphan enzyme in humans.

How is it possible that these orphan enzymes weren’t sequenced already?

There are many reasons that orphan enzymes were not sequenced. The single biggest factor is age. As described in Yannick Pouliot’s initial survey of orphan enzymes, the average age of first publication for an orphan enzyme is in the 1970s. The majority of orphan enzymes were experimentally characterized well before the development of methods such as mass spectroscopy based sequencing that made it relatively affordable and simple to determine the sequence of a purified protein.

Orphan enzymes may also occur because final purification or sequencing is especially complex, such as in the case of a membrane protein with many spans.

Sometimes, enzymes were not sequenced because the research group simply was not funded to take the work to that stage, or their own research goals were met simply by evaluating the enzyme activity without carrying out final purification and sequencing.

How do I report a new orphan enzyme?

We welcome submissions of new orphan enzymes (it may help to read What is an orphan enzyme? to see if you are dealing with an orphan enzyme). If you are submitting a new orphan enzyme, please include as much of the following information as you know:

    • Every name or synonym for the enzyme activity
    • The chemical transformation catalyzed by the enzyme
    • Any identification data you know about the enzyme, including:
      • Molecular weight(s)
      • Isoelectric point
      • Chemical kinetics
    • Citations for publications describing the characterization of the enzyme

If you have copies of any of the relevant publications for your enzyme, please include those using the “attach papers” option. The form allows three papers at a time, but feel free to use the form more than once if you have more than three papers to submit.

How do I contribute information about existing orphan enzymes?

We definitely appreciate new information about existing orphan enzymes. All of the guidance above for reporting a new orphan enzyme applies.

Please don’t be shy about correcting us! Our team has worked its way through thousands of publications, patents, and database entries. Mistakes (or simply different conclusions) are inevitable.

What if we have a sample of an orphan enzyme and would like to contribute it for sequencing or testing?

Excellent! If you have a sample of an orphan enzyme (or can produce more sample at will) please contact us. It is especially helpful it you can tell us:

    • How much you have or can make
    • Were there any experimental roadblocks that prevented sequencing of the orphan enzyme in the past?

Although our project currently does not have a funded lab component, it is essential that we identify those “on the shelf” samples that are one step away from identification (see our Publications for why this is so important). We plan to connect researchers with samples with specialists in protein sequencing to get more of this sequence data “on the books” for future research.

What are some resources I can use in resolving an orphan enzyme?

Take a look at our Tutorials page for guidance on how to resolve orphan enzymes.

In addition, there are many community resources that are helpful or essential in resolving orphan enzymes. Here are some you may want to use:

    • UniProtThe source of comprehensive, high-quality protein function information linked to sequence.
    • NCBI Protein database – Access to a comprehensive list of deposited protein sequences.
    • Enzyme Commission – This page explains how enzymes are given EC numbers, what those numbers mean, and more explanation about the EC system. It also provides access to all the enzymes in the EC system with descriptions and citations for their supporting literature.
    • The ENZYME database – ENZYME provides a cleaner interface to the enzymes in the EC system, with search options by enzyme, EC number, compound, and more.
    • RCSB PDB (Protein Data Bank) – The comprehensive database of protein structures. This is also sometimes the only place that we find sequence data for certain enzymes.
    • BRENDA – An extensive database of curated enzyme data with a host of data linked to citations. BRENDA was our first stop when we were evaluating orphan enzymes with EC numbers.
    • MetaCyc – A comprehensive metabolic database that sometimes includes links or clues to find sequences for orphan enzymes.
    • ORENZA – The original orphan enzyme database.