OOL XIII - The "Zymes"

Let us quickly review what we are doing and why. We are
investigating the chemical basis for specific catalysis in
biochemistry. Catalysis is important because life is an
open thermodynamic system, and because metabolism seems to
be a prerequisite for other aspects of life, such as genetic
systems based on anything as complex as nucleic acids.

But catalysis must be specific in the sense that the catalyst
speeds particular reactions, not just particular kinds of
reactions. Specificity can be inherent (that is, a trait
of the catalytic molecule). However, even with modest
inherent specificities, we can still achieve acceptable
effective specificities if the metabolic system as a whole
restricts the available substrates.

Here, in a nutshell, is the reasoning behind my intuition
that life must have been autotrophic in its origin. In a
heterotrophic theory, there can not have been any original
limitation on the available substrates. Hence, if the
original biological catalysts had only modest inherent
specificities, then they could have achieved only modest
effective specificities. But in an autotrophic origin, you
may be able to achieve high effective specificities from
the start, even with modest inherent specificities. And
this high effective specificity provides the basis in
precision for avoiding the Eigen error catastrophe and
thus allowing the eventual evolution of high inherent
specificities.

But, to get the ball rolling, you need at least modest
catalytic activity and at least modest inherent specificity
in your catalysts.

In the previous posting, based on the evidence of modern
enzymes, we identified three distinct mechanisms contributing
to catalysis.

* Reduction in activation entropy - This is accomplished by
the enzyme binding substrates and co-substrates before
the reaction takes place. It is in this mechanism that
specificity is accomplished. The enzyme binds its cognate
substrates more tightly that it binds non-cognates. This
binding takes place in the portions of the substrate
other than the reaction site.

* Reaction site design - Includes both geometric and solvation
aspects. The geometric aspect involves having the enzyme
bind more tightly to the transition state of the reaction
than it binds to substrates and products. The solvation
aspect is most frequently a matter of excluding water from
the active site. If the reaction requires that a weak
base (such as a carboxylate) be transformed to an acid
before the reaction takes place, then this can happen more
easily if water is excluded.

* "Electronics" - This term is non-standard. I intend it to
include those aspects of catalysis that involve getting
the electrons to the right place, as opposed to getting
the atomic nuclei to the right place. Usually, this involves
supplying channels for electron flow so that some electrons
can be "stashed away" out of the way while the nuclei are
moved into position, and then the electrons can be rapidly
redeployed to the places where they are needed for the
reaction proper. Anyone who has looked at a variety of
reaction mechanisms should understand what I mean by this.

I claimed that "electronics" is usually the responsibility
of co-enzymes, rather than of enzymes. I include among the
coenzymes such things as heterocyclics like thiamine, simple
transition metal ions like the iron in aconitase, sulfhydryls
like CoA, metal-sulfide clusters, and even protein-based
cofactors such as glutathione and the cytochromes.

It should be clear that the substrate-enzyme binding energy
is crucial to enzyme action. It provides the reduction in
activation energy directly. Since good reaction site design
will frequently repel the substrate, it is the positive binding
energy of the rest of the substrate that must "pay for" the
negative binding energies of the reaction sites. And finally,
even if it is co-enzymes that provide the "electronic magic",
it is the binding energy of co-enzyme to enzyme that brings
the magic to bear.

Let us define a "zyme" as any biomolecule which provides the
same function of specific catalysis as is provided by
enzymes. As examples of zymes, we have enzymes and ribozymes.
But there must have been some biomolecules that served this
function before ribozymes - let us refer to them as oozymes.
(In my scenario, the only kind of oozyme was the "lipozyme",
but we will be more inclusive here and contemplate scenarios
in which there may have been various kinds of oozymes.)

Can we develop some insights into ribozyme and oozyme mode
of operation from our analysis of enzyme mechanism? It is
clear that protein enzymes have the ability to generate plenty
of substrate binding energy for all but the smallest substrates
and co-enzymes. The only kinds of molecules which they can't
bind well are the very small inorganic molecules such as
H2, H2O, CO, N2, H2S, NH3, etc. But these molecules can be
bound by transition metal co-enzymes, so a protein based
metabolism suffers few limitations.

Ribozymes also can generate significant binding energies for
substrates and co-enzymes which are also nucleic acids, but
they have more difficulty with the smaller and somewhat
hydrophobic substrates, such as isoleucine and leucine. That
is why I suggest that RNA world metabolism was based on
substrates bound to RNA carrier molecules. It may also be
noted that ribozymes may find it difficult to do some kinds
of "solvation" catalysis at the active site (though Steven
Benner might dispute this).

What about oozymes? Well, if the oozymes are macromolecules
which are the products of some kind of polymer genetics, then
there doesn't seem to be any particular limitation to their
abilities. But let us assume that there was no polymer
genetics. What can we accomplish with oozymes built from
just a handful of "building blocks" or just one?

It seems clear that any such molecule would not be able to
generate the large specific binding energies that can be
deployed by ribozymes and enzymes. In fact, it is not at
all clear that such molecules would be able to bind anything
at all. You need at least 4 or 5 hydrogen bonds worth of
binding just to pull a substrate out of solution, inducing
it to give up its entropy. So it would seem that any kind
of pre-polymer-genetics oozyme is simply impossible.

Is there a loophole in this? Well, perhaps there is a way
of reproducibly constructing macromolecular oozymes without
polymer genetics. This seems to be the plan of most
heterotrophic theories of the origin - particularly the
"protein first" theories. But this idea is not very attractive.

Instead, we will look at a theory that permits binding to
substrates without paying the entropy price to pull them
out of solution. We will look at a theory in which all of
the organic substrates have already given up most of their
entropy in exchange for a non-specific binding energy provided
by the system as a whole (rather than by the zyme). In this
theory, the binding energy between zyme and substrate, or
between zyme and co-zyme, can be just a few hydrogen bonds.
Of course, this would mean that the binding cannot be
exquisitely specific, but perhaps it can be specific enough.

That theory is lipozymes. More detail in the next posting.


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