Posted by: Dan | September 21, 2007

Small Molecules at the Beginning

Small molecule ligands and the protein domains which interact with them represent an insightful point of view on both drug discovery and on the basic universal biochemistry, at least for extant life. A recent study in the journal Genome Biology shed a bit more light on this available data. Hong-Fang Ji and colleagues write:

By examining 2186 well-defined small-molecule ligands and thousands of protein domains derived from a database of druggable binding sites, we show that a few ligands bind tens of protein domains or folds, whereas most ligands bind only one, which indicates that ligand-protein mapping follows a power law.

About evolutionary-based interpretations, they conclude:

Some nucleotide-containing ligands, such as ATP, ADP, GDP, NAD, FAD, dihydro-nicotinamide-adenine-dinucleotide phosphate (NDP), nicotinamide-adenine-dinucleotide phosphate (NAP), flavin mononucleotide (FMN) and AMP, are found to be the earliest cofactors bound to proteins, agreeing with the current understanding of evolutionary history.

On this, Morowitz has more to say in Beginnings of Cellular Life:

If one considers all low molecular weight compounds (fewer than 500 daltons) that can be made from carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur, the number is immense. Yet from this potential group, a very small subgroup is actually used by living systems. That list of compounds, which should include all the universally used ones, contains on the order of hundreds of substances…

This group of compounds should be of heuristic value form the point of biochemical evolution as well as studying biochemical control. In addition, the experimental list is a prerequisite to attempts to find a thermodynamic, kinetic, or other physical basis for the choice of particular biochemical metabolites. (pgs 44-45)

What Morowitz is saying, and I agree with, is that this list of universal biochemical compounds represents chemicals that (a) are reasonably accessible from pre-existing metabolic pathways; (b) have utility in either chemical storage energy in covalent bonds, or have some structural/associative function; and (c) via metabolic cycles (within cells, and beyond them – e.g., fixation) can perpetually manifest as a life cycle of sorts, upon which selection can act.

That last item is the crucial one – can the form and function of metabolic cycles be selected for in proto-cells? Chemostats, I think, provide justification to answering ‘yes,’ as do genetic algorithms or digital organisms (e.g., Avida).

And so we have a modern version of the “Primordial Soup” hypothesis.

  • Ji HF, Kong DX, Shen L, Chen LL, Ma BG, Zhang HY. Distribution patterns of small-molecule ligands in the protein universe and implications for origin of life and drug discovery. Genome Biol. 2007 Aug 29;8(8):R176.
  • Morowitz, Harold J. (1992) Beginnings of Cellular Life: Metabolism Recapitulates Biogenesis


  1. I just wrote a blog entry about the ironic claim of Michael Behe that, in the ten whole years since he wrote his previous book, scientists had not offered a comprehensive explanation of the bacterial flagellum to his satisfaction.

    It is such a stark contrast between ID, which has its mind made up from the outset, and actual scientific research that continues to push back the boundaries of our knowledge.


%d bloggers like this: