Complexity in Living Things

_Nature_ v. 432, 4 Nov 2004, p. 118, "Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase" by Thoma _et al._ shows yet another especially fine example of complexity in living things. Oxydosqualene cyclase, also known as OSC or lanosterol synthase, is just one of many highly complex molecular machines in cells. This article has a couple examples of technical phrases that sound as much like science fiction as science fact.

"In a highly selective cyclization reaction" this massive molecule takes a very zig-zag-y molecule and connects some dangling pieces to turn it into a molecule with four rings and "seven chiral centres." This reaction is also called a "highly exothermic cyclization reaction" and a "Highly exergonic cyclization reaction." I'm not sure if there's a difference between "exothermic" and "exergonic" -- I think they both mean that heat energy is released/generated in the process. The "complex cyclization cascade" has been studied for about 50 years, but "it is still not fully understood how the enzyme catalyses the reaction."

The molecule itself is made "of two ([alpha]/[alpha]) barrel domains that are connected by loops and three smaller [beta]-structures." At one end is a special membrane insertion region to anchor the molecule to the cell membrane. The insertion area is tilted or to one side of Domain 2, so the molecule lies along the membrane surface, with a special amino-terminal seqence region on the far side, in the cleft between the two domains.

"The catalytic mechanism for the polycyclization reaction involves several reaction steps." The molecule that OSC works on "adopts a pre-organized chair-boat-chair conformation" to start with, and then "Protonation" (adding a hydrogen ion) "triggers a cascade of ring-forming reactions." This sounds like one simple step sets off a sequence as uncomplicated as a row of dominoes falling down, but there's more to it -- "Skeletal rearrangement...through a series of shifts and a final deprotonation steps." Furthermore, "Product specificity and high stereoselectivity are believed to be achieved by several factors: first, forcing the substrate" (the original oxidosqualene molecule) "to occupy a prefolded conformation, second progression of the reaction through rigidly held, partly cyclized carbocationic intermediates, and last, stabilization of the intermediate carbocations by cation-[pi] interactions, thus preventing early truncation of the cyclization cascade..."

It sounds like this bit of biological nanotechnology performs the chemical equivalent of forcing a landslide to pile up into the shape of a hut, a process that scientists have been studying for five decades without fully comprehending -- and we're supposed to believe in came about by chance?

Until Next Time,

David Bump
Philippians 3: 13 Brethren, I
count not myself to have
apprehended: but [this] one thing
[I do], forgetting those things
which are behind, and reaching
forth unto those things which are
before, 14 I press toward the
mark for the prize of the high
calling of God in Christ Jesus.

http://home.att.net/~david.bump