Cancer Initiation: Glycosylation patterns of extra-cellular matrix proteins as fossils of an earlier metabolic state

Sunday, December 22, 2013

Glycosylation patterns of extra-cellular matrix proteins as fossils of an earlier metabolic state



As mentioned in the previous post, regarding the loss of expression and predicted function of PKD 1, I feel it is probably time to make a note, that to my knowledge has not been made, and is now overdue. The question we propose to answer is "why to extra-cellular matrix proteins so often make use of carbohydrates, or polysaccharides for signaling, when in fact, the traditional view is that proteins do most of the cells signalling work?"
  In short, the answer is that these "sugar" molecules are remnants from a period in the history of evolution that existed before proteins were being manufactured by cells, an "earlier metabolic state" so to speak. This is the term chosen by Harold B. White in his pivotal paper [1] concerning the molecular structure of coenzymes that are used by the cell in another cellular process which dates from "archaic" times, the Krebs cycle and oxydative phosphorylation.
   Two somewhat well known enzymes, at least to students who have taken  a biology course in which ATP production has been  discussed ,  are NAD and FAD .  The D in these stands for dinucleotide. What the "molecular fossils" paper noted was that these prosthetic groups bore more similarity to nucleotides than proteins, and they were necessary for their respective proteins to be functional. The structure poses the question "Why would nature contrive a system like this?" Scientists seek to define systems in terms of rules and laws, and nature seems to randomly through chaos into our otherwise neat theories.  The answer Dr. White proposes is that it is a "molecular fossil".  It is an artifact from a time period before the emergence of proteins, an "earlier metabolic state."
   At the time that "molecular fossils" was published it received little interest. Appearing in 1976, was quite a bit ahead of its time. After a decade or so went by, more molecular evidence had accumulated and Walter Gilbert summed it up in his paper coining the term "RNA World" to further define White's "earlier metabolic state".[2]   Two of the most pivotal citations ( in my opinion ) were those of White and Thomas Cech, the discoverer of  small enzymatic RNA molecules, or "ribozymes" in his terminology.
   Much has been said about the RNA world hypothesis. It has created a virtual assembly line of Nobel Prizes, including one for Cech.
   Possibly more important - at least for the sake of this note, is that there are many bio polymers that appear to be "archaic" and  have potential to shed light on the creation of life in the manor of molecular fossils, and also have medical significance.
  A systematic approach would be to start with the question "What are the most primitive,  or archaic processes that could be defined as "metabolism",  or a "metabolic state?"  The first answer might be to harness a source of energy from the environment. For this system, we already have a consideration since the function of the citric acid, or Krebs cycle is to generate ATP, the energy currency of the cell. For the contribution of the description of an "archaic" system, we have Dr. White. to thank.
   Next, at the risk of being too obvious,  we must have a system to separate, or contain those precious little cell contents. As a review, the energy generation system implemented by the citric acid cycle is entwined with the cell membrane, and "cell wall" of the cells mitochondia. To function, a cell membrane must exist which is impermiable to electrons and ions, so that a concentration and charge gradient can be obtained. It is actually the gradient that drives the ATP synthetase, so an enclosure of some type is implied. Our most commonly known enclosure system is the phospho-lipid bilayer known as the cell membrane. I don't know that the cell membrane has been officially listed as archaic, perhaps because it seems so obvious, but there are alternative candidates. Many bacteria make use of "lipo-polysacarride" cell walls in addition to membranes. There are alternatives for a precise structure.
    Next, cellular information must be stored, and it must be passed from generation to generation. This function has been covered beyond what is even practical to consider. In short, RNA can be coerced into performing many functions related not only to information storage, but implementing functioning enzymes. For more info, search on the key word "RNA World".
   Once our primoridal cells accumulated information, and tucked it away in their RNA, the next thing they needed to do was protect it. There is no use accumulating cool information, only to loose it to a harsh sea environment. Presumably, if not obviously, they commenced experimenting with "picket fence" technology.
  Presumably, their experiments were along the lines of what they knew best, making polysacarrides. One sugar which seems to have been particularly successful since archaic times is fucose. Fucose also goes by the name fucose sulfate, or fucoid. It is known as an "exopolysaccharide" due to its primary location outside the cell membrane. It is a common foundation of marine algae such as kelp. Presumably, the molecular structure of fucoid interacts with the aquatic environment in a way which is protective. Not coincidentally, kelp and its exopolymers of fucose are a good source of industrial emulsifiers.
   So ... Nothing controversial yet....
   So now we must ask "did these primitive inhabitants of the early earth ever decide they had to get together and exchange genetic information with each other?" In other words, is swapping genes a valid behavior in an earlier metabolic state?"
   First we must consider the possiblity of "no". Hmm.
    On the other hand life as we know it seems to be the result if continuous hybridization among various environmentally  selected information accumulations. It seems unlikely that we could deny anything we could call "metabolic" the property of genetic hybridization with its contemporaries. Our whole concept of "advancement" seems to be based upon systematic hybridization.
   The presumption of systematic hybridization in an environment where cellular life must:
  1. Be able to establish and hold chemical, ionic and electrical gradients
  2. Defend themselves from the chemical forces of the environment
  3. Defend integrity of accumulated informational ( nucleotide ) material
seems to imply that that a lock and key recognition mechanism was a valid foundational function of our "archaic" life form. A "wet handshake" so to speak. So what evidence of this may we point to today?
  The point of contact in today's most common hybridization mechanism is the egg-sperm interaction.
 It has been shown that the "receptor for egg jelly"  (REJ) protein on the acrosome of the sperm is
"keyed" to intract with "fucoidin", or "fucose sulfate of egg jelly" in the terms of Vacquier and Moy [3].
  For the reasons mentioned, this is a "non-traditional" interaction in that it involves polysaccharides and their recognition, and it involves a polysaccharide which has a known archaic function ( cellular protection). It is also a reaction that is preserved in modern life, the REJ- fucose sulfate reaction seems to qualify as a "molecular fossil".
  As a generally accepted principle, new genes form by duplication of existing genes, and then evolving
 more slowly as a function of natural selection in their environment. It can be speculated ( hypothesized ) that the REJ gene of the sperm, our most primitive cell, has under gone one or many duplications to give rise to the PKD1 gene. We known form gene sequence analysis that PKD1 contains an extra-cellular "suREJ" or sea urchin receptor for egg jelly domain.  We apparently can thank Vacquier, Moy and their sea urchin laboratory for naming this domain, and identifying the associated duplications in the sea urchin as well as the human species [4].
   PKD1 is a gene that seems to be found in all "epithelium". Epithelium has the defining property that it is a sheet of cells which are bound to a "basal membrane". The basal membrane in turn contains highly glycosylated extra cellular matrix proteins. Most likely ( but unproven ) , fucoid type decorations in the
basal membrane are key players in cellular recognition of the membrane, and polarization development.
  In this case, PKD1 would be a second generation molecular fossil, that is a molecular fossil by duplication of the REJ gene. Likewise, the basement membrane of epithelium can be thought of as a "display decorated by polysacharide fossils for the purpose of large scale structural organization."
  PKD 1 has something that most research targets in the RNA world don't have. That is, a common severe medical condition. PKD, itself as an acronym for Polycystic Kidney Disease. Thus, spending large amounts of medical foundation money on its function would actually be justified.
  Conversely, a recent announcement by a South Korean group has made obsolete most of what was previously known of the pathological dynamics  of PKD 1.


References

[1] White H.B. (1976). Coenzymes as fossils of an earlier metabolic state. Journal of Molecular Evolution,7, 101-104 [Abstract]

[2]  Walter Gilbert  Origin of life: The RNA world Nature 319, 618 (20 February 1986); 

[3] Vacquier VD, Moy GW.
The fucose sulfate polymer of egg jelly binds to sperm REJ and is the inducer of the sea urchin sperm acrosome reaction.
Dev Biol. 1997 Dec 1;192(1):125-35.

[4] Gunaratne HJ, Moy GW, Kinukawa M, Miyata S, Mah SA, Vacquier VD.
The 10 sea urchin receptor for egg jelly proteins (SpREJ) are members of the polycystic kidney disease-1 (PKD1) family.  BMC Genomics. 2007 Jul 13;8:235. [PubMed Central]

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