Pathway discovery tools (IPA, GENEGO, Pathway studio) for non-pharma analysis ?

Question

[Brett]

I am tasked with finding a pathway solution tool for a commercial environment. This is not my area of expertise and I would appreciate any insight you guys could give.

I am looking for the best tool to integrate bacterial genomes/data to help discover novel activities and microbial pathways. Within this it's not just creating novel pathway networks, but automatically becoming alerted, when lets say a new publicly available genome has genes that match your custom pathway (based upon GO annotation or similar).

It seems on the face of things commercial tools (ingenuity IPA, GENEGO, Pathway studio) are close to what I wish to achieve, but they are very much aimed at pharmaceutical market (databases of drug targets, human genome analysis etc )

How well do these cope with chemicals/intermediates that are not related to drug targets? or enzymes that may catalyse a related compound using hijacked pathway.

Do they cope well with bacterial pathway analysis?

Even just general pros and cons of software out there would be a big help

Or are there other solutions? Using several tools in combination? PATHologic and metashark look interesting

Any insight, solutions or links to papers/documentation would be great!

[Devon Ryan]

For what it's worth, you can demo IPA for a little while for free and just directly gauge how well it works with your data.

Answer 1

[Chris Evelo]

I am afraid I only have partial answers for you.

You mention that you work in a commercial environment. But that does not necessarily mean you need to use commercial tools or pathways, or does it?

If I read your question correctly you are not really asking about pathway tools, you are mainly asking about the pathway content used with the tools. Now commercial providers tend to offer one with the other, but that is not a necessity. You can often create or import your own pathways. Our own tool, PathVisio, for instance, can work with WikiPathways pathways as well as other pathways converted to the same format (Reactome, KEGG) or any other available in BioPAX format. Commercial tools also often allow addition of your own pathway collection.

That of course doesn't help you too much, since now your question will probably be whether bacterial pathways are available at all. I checked and we only have a few of those on WikiPathways. You can of course create more, but that might be more of a task that than you want to take up. You might consider it if you are working on a specific species. The worm and tuberculosis communities for instance are doing a fantastic job on that.

The metacyc project is really interesting for creation of species specific pathways. You might want to check whether a cyc for your specific species already exists, or if not create one. We have done some work in the past on automatic conversion of plant pathways from metacyc (tomato and arabidopsis) to WikiPathways format, but that is going slowly mainly because of lack of funding. It is doable however. So if this is important to you you might want to first create the cyc pathways and then work on the conversion.

You also ask about interacting compounds. These will usually not be in pathways at all, except for endogenous metabolites, and indeed drugs now and then. So what you will usually want to do is use an external resource to connect interacting compounds to (proteins in) pathways that are already there. There are several ways to do that, for instance using the Open PHACTS API to get compound-protein interactions (which will usually come from ChEMBL in that case). But that might go beyond your question.

[Brett]

Thanks for brilliant reply Chris. In an ideal world I would like a program that biologists could use, that's partly why I have focused upon commercial software. The other half is while I can use free software it usually takes months to get legal approval. But both those issues though really come second to the best scientific solution.

Your interpretation of my question was pretty spot on (tools on surface seem to be able to do as I wish, but its really what content they can offer). Part of the problem though was my lack of understanding with pathway generation.

By reading your post it seems I was under the wrong impression of how this is achieved, I had thought that new bacterial genomes got automatically mapped onto metacyc/kegg and then manually curated. I had hoped (it seems unrealistically) that these commercial tools would draw on multiple sources (public and private) and integrate it all in one semi- automatic solution (perhaps even do subtractive differentiation) . The goal being that as soon as a potentially interesting new pathway became available (eg by chemical structure), or potential candidate enzyme that may fit my custom pathways (by homology, Go annotation) I would become alerted for further investigation.

As such I can't work on a specific species, as the aim is to concentrate on approx 100 non-natural substrate/products/intermediates and discover which bacteria may act upon them (as they become available), to help generate a new pathway.

At the moment I rely upon databases I generate myself with inspiration from EC-Blast/cyc databases to generate novel pathways. But the best solution is to start from the best enzyme in nature/high jack native pathways (in whatever species that may occur).

It's a shift in this emphasis from discovery to finding the optimal solution (or other routes to same product) which drives using pathway centric approach to help generate the best solution.

I realise that there is nothing out there that can do everything I want to it to achieve but I was hoping that these tools might go a long way in helping to achieving that.

Openphacts was a particularly good tip!

Answer 2

[cdsouthan]

It might seem off the wall to suggest experimentation as an answer but if (a big if I know) the bugs your interested are culturable comparative metabolic profiling is a more direct option. Unfortunately new metabolilte/enzyme pairings are few on the ground (as came up in this post). I cant quite work out the commercial angle on your 100 "chemistry suspects" but what you could do in silico is explore their similarity neighbourhood in PubChem in some detail. If your lucky you might connect to metabolic clues or even a natural product paper that links you to an organism. Note also that the metagenomic databases are stuffed with new strange enzyme sequences that will keep pathway annotators and experimental enzymologists (and structural biologists) busy for years.

Answer 3

[Larry_Parnell]

EcoCyc is something that you should look into. It's focus is E. coli, but can be useful for other bacterial species. A partner database is BioCyc, a collection of 3563 Pathway/Genome Databases (PGDBs), with tools for understanding their data.