Natural products

Do a Google search and you’ll find all sorts of stuff claimed to be “natural products” — amazingly, some of them even are “chemical-free”! Now seriously. To quote IUPAC’s 1999 recommendations [1],

The nomenclature of natural products has suffered from much confusion.

That does not surprise me. What is surprising, however, that neither these nor the previous recommendations [2] tell us what the “natural products” are. Ditto the Gold Book. It may define terpenoids as “natural products and related compounds formally derived from isoprene units” but the natural products go without explanation. (Nor is it clear what “related compounds” are.) The very same Gold Book says that natural graphite is “a mineral found in nature”. Therefore, “natural” means “found in nature”. Right? Right. Is natural graphite a natural product? I am not sure.

Let us look in Webster then:

A chemical substance produced by a living organism; — a term used commonly in reference to chemical substances found in nature that have distinctive pharmacological effects. Such a substance is considered a natural product even if it can be prepared by total synthesis.

Is that any better? Both dioxygen and nitric oxide are produced by living organisms and have rather distinctive pharmacological effects, yet most chemists would hesitate to call them natural products. In The Concise Oxford Dictionary, the first definition of “natural” is

existing in or caused by nature; not artificial.

Of course human beings are parts of nature, but maybe this negative definition, “not artificial”, is indeed most useful?

In ChEBI, natural product (no definition so far) is an organic molecular entity (so no O₂ or NO here) and includes the following classes:

• alkaloid
• carbohydrate
• cyclitol
• heterocyclic natural product
• lipid
• peptide
• phenylpropanoid
• polyphenol

On the first glance, nothing looks particularly disturbing here. But I see a bit of a problem with ontology. First, all is a children of natural product have to be natural products. What if we have, say, (artificially) fluorinated carbohydrates? Are they still carbohydrates? If no, then the True path rule is broken. If yes, then some “unnatural” compounds will be considered natural products. I don’t mind that — perhaps that will cover “related compounds” (whatever they are) nicely.

Second, CHEBI:33243 belongs to chemical entity ontology, which is (or at least it should be) purely structure-based. The origin does not enter here. There is no such thing as intrinsic “naturalness” in a natural product molecule: natural product remains a natural product even if (artificially) prepared by total synthesis.

Natural products often are equated with secondary metabolites. This does not seem right. In ChEBI, secondary metabolite (“A metabolite that is not directly involved in the normal growth, development or reproduction of an organism” — another negative definition?) belongs to role ontology. (The role ontology sounded such a good idea at the time... no, don’t get me started.) At best, one can say some natural products have role “secondary metabolite”. Yuck.

To summarise: “natural product” appears to be a rather useless top-level term. Let us look at the sources of natural products: plants, fungi, bacteria, animals. What if, instead of saying “fungal natural product”, we say “fungi-specific compound”? In this case, we discard primary metabolites, other simple compounds found just about everywhere in the universe and are left with exactly what we want: molecules isolated from and specific for fungi.

Or are we? Antibiotics, naturally synthesised by fungi, are not naturally found in humans. But when we take them, they are naturally metabolised in our liver and eventually excreted with urine. Are these metabolites the natural products? If yes, are they fungal or animal or neither?

1. Revised Section F: Natural products and related compounds (IUPAC Recommendations 1999). Pure Appl. Chem. 71, 587—643 (1999).
2. Nomenclature of Organic Chemistry. Section F: Natural Products and Related Compounds. Recommendations 1976. Eur. J. Biochem. 86, 1—8 (1978).

It’s elementary

According to IUPAC’s Principles of Chemical Nomenclature [1],

An element (or an elementary substance) is matter, the atoms of which are alike in having the same positive charge on the nucleus (or atomic number). In certain languages, a clear distinction is made between the terms ‘element’ and ‘elementary substance’. In English, it is not customary to make such nice distinctions, and the word ‘atom’ is sometimes also used interchangeably with element or elementary substance. Particular care should be exercised in the use and comprehension of these terms. An atom is the smallest unit quantity of an element that is capable of existence, whether alone or in chemical combination with other atoms of the same or other elements.

You can’t help noticing the circular nature of these definitions: An element is matter, the atoms of which have the same atomic number; while an atom is the smallest unit quantity of an element. And what are “atoms of the same or other elements” if not just “any atoms”?

Of course it is not helpful that ‘element’ is used for either ‘elementary substance’ or ‘atom’. The ChEBI solution was to get away from ‘element’. Instead, there are either atoms or elemental molecular entities. These belong to different branches of ontology, so they should not really be confused. Or at least, that was the idea.

In ChEBI, ‘elemental’ applies to any class of molecular entities which consist of only one type of atom, be they mono- or polyatomic. For instance, elemental oxygen can be mono-, di- or triatomic. On the other hand, the oxygen atom can be part of a non-elemental molecular entity.

If there is a scope for confusion, people will get confused. Here’s a question I heard on more than one occasion: what is the difference between monoatomic oxygen and oxygen atom? After all, any form of monoatomic oxygen, viz. oxide(•1−), oxide(2−), or neutral monooxygen, can also be referred to as an ‘oxygen atom’. Ditto any of the monooxygen groups: oxido (—O⁻), oxo (=O) and oxy (‒O‒). The thing is, they belong to different universes (which, properly, should be made disjoint):

• monoatomic oxygen is a monoatomic entity is a molecular entity
• monooxygen group is a group
• oxygen atom is a atom

A group does not exist on its own: it is always a part of polyatomic entity and consists of at least one atom plus at least one bond. Monoatomic entity consists of one (and only one) atom and does exist on its own. Since we need ‘atom’ to define both groups and molecular entities, it is a good idea to keep atoms in an independent, disjoint branch.

1. Leigh, G.J., Favre, H.A. and Metanomski, W.V. Principles of Chemical Nomenclature: A Guide to IUPAC Recommendations. Blackwell Science, 1998, p. 3.

Ontology and reality

One of these days, I keep promising myself, I am going to publish something incredibly clever about chemistry, ontology and/or chemical ontology. Then again, I need some incentive to do so, and there’s none in my view. In the meantime, I am happy that somebody else has bothered to write a paper dealing with so-called “realist” approach to ontology [1].

Personally, I never cared much about the “reality” as used in context of OBO Foundry Principles [2]:

Terms in an ontology should correspond to instances in reality.

Worse still is its “corollary”:

Ontologies consist of representations of types in reality — therefore, their preferred terms should consist entirely of singular nouns.

(Why? Does “reality” really consist of singular English nouns?)

Now Lord and Stevens confirm my gut feeling that “realism” (the authors take care to clarify that “realism” in [1] stands for “realism as practiced by BFO”) applied to ontology building often results in unnecessary complexity. Everybody who ever studied physics (or English) in school would agree that expression |dr/dt| is much better definition of speed than the one provided by PATO: “A physical quality inhering in a bearer by virtue of the bearer’s rate of change of position”. To quote [1],

It makes little sense to replicate the models of physics using English instead of a more precise mathematical notation.

Alas, this is exactly what BFO (and most of OBOs) are trying to do. By going “where science has gone before” without learning the language of the science, BFO & Co. keep reinventing the square wheel.

OK, what about chemistry? Chemistry has developed its own language which makes the plain-text definitions for molecular entities redundant. The 2-D diagram (connectivity) defines the molecule of interest better than a paragraph in English. In theory, the systematic name should provide the exactly same information (and thus to be usable as a definition). However, the systematic names for even relatively small molecules often are too complicated to be widely (or ever) used.

Take the systematic name (a) for beauvericin. You are extremely unlikely to either hear it (because it is more or less unpronounceable) or see it (it takes more than one line of text, which is annoying). More importantly, there is a certain limit of molecular complexity above which the systematic names (according the existing nomenclature rules, that is) simply cannot be generated. On the other hand, the diagram (b) is both beautiful and useful.

(a)	(3S,6R,9S,12R,15S,18R)-3,9,15-tribenzyl-4,10,16-trimethyl-6,12,18-tri(propan-2-yl)-1,7,13-trioxa-4,10,16-triazacyclooctadecane-2,5,8,11,14,17-hexone
(b)

Not only are the 2-D diagrams self-defining, they provide all the information needed to build the consistent ontology for molecular entities. With a few simple rules, the ontology will build itself from scratch, I promise. But this is a topic for another post.

1. Lord, P. and Stevens, R. (2010) Adding a little reality to building ontologies for biology. PLoS ONE 5, e12258.
2. OBO Foundry Principles.

The Royal Society of Chemistry News

By some amazing coincidence, the same day as I have resuscitated this blog, the Royal Society of Chemistry has published the first issue of Metallomics, “a new journal covering the research fields related to biometals”. Good news is that the first issue is free. Check the “enhanced HTML articles” (for instance, this one) which provide “chemical ontology terms” which are nothing else but ChEBI ontology terms, with links to ChEBI.

On a lighter, but still metal-related note, the article on RSC blog entitled Gold saved! lists a winner and four more solutions to “The Italian Job problem”. Cool.