Isomers, Prions, Homonyms, Necker Cubes, Us and the Universe - Part 2 by Gaurang Bhatt, MD SignUp
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Isomers, Prions, Homonyms, Necker Cubes, Us and the Universe - Part 2
by Gaurang Bhatt, MD Bookmark and Share
 

To anyone who read part one and is somewhat unclear, the theme of this series is that appearances are deceptive and all that glitters is not gold. We have all heard stories in which a rope is mistaken for a snake in poor light. The message of my series is meant to show that truth is stranger than fiction.

As children we all played with a kaleidoscope and every turn produced a new design, The glass beads remain the same in color and number but their rearrangement viewed through a prism yields a different design.

Constitutional isomers are like that. The subtlety is that identically connected atoms give stereoisomers which are enantiomers, diastereoisomers or cis-trans isomers. These are handled differently by living organisms which show preferences between right and left sided compounds. In future articles we will try to show that we and the universe also have a chirality or handedness.

To understand the puzzle of Prions we need to know that the basic molecules of life capable of faithful copying with rare mistakes, are the nucleic acids RNA and DNA. While RNA may have been the earlier and DNA the newer molecule, these both can be mutually copied from each other. The virus for HIV and other primitive viruses use RNA molecules for their genetic code. When they infect us they hijack our cellular machinery and synthesize a DNA molecule using their own RNA as a template. On the other hand our cells normally make RNA copies of our DNA and send them to organelles called ribosomes where they are used as template to make corresponding proteins which are a chain of amino-acids. The RNA to DNA and DNA to RNA both involve nucleic acids and the process is called transcription. In other words the language of both is the same but it is like one message is written in italics and the other in block letters. This process is reversible. When RNA is used to make a protein, the language is amino-acids and is different, so this process is called translation. Crick who discovered DNA and its functions with Watson propounded a classic dogma that one can go to proteins via RNA from DNA, but the return path from protein to nucleic acids is forbidden and not traversable. Thus any infection by viruses or bacteria or infestation by parasites require them to insert a copy of their nucleic acid genome into the cells of other living organisms.

There is a Prion disease of sheep called Scrapie in which infected sheep scrape their hide to quench an itch and develop unsteadiness and brain degeneration. Two separate Nobel prizes were given to Gajdusek of NIH and Prusiner of UC San Francisco for their work on Prion diseases. There is a CNS disease called Kuru which is prevalent in the Fore people of the central highlands of New Guinea. They indulge in ritual cannibalism of killed enemies and some dead relatives. The men tend to eat the meatier parts while the women and children end up eating the less desirable parts like the brain and spinal cord. Gajdusek noticed a disproportionately high incidence of the disease amongst women and children and made the connection that the transmission was by consuming diseased nervous systems.

An earlier occurrence of another degenerative nervous system disorder called Creutzfeld-Jakob disease in children who had received growth hormone injections and some adults who had received corneal or other allo-grafts helped to clarify another mode of transmission. In those days human growth hormone injections and transplanted grafts were obtained from cadavers. This disease causes the brain to show multiple holes like a sponge and is known as a spongiform encephalopathy. Interestingly very rare cases of CJD are inherited in families as is another prion disease called Fatal Familial Insomnia. Finally the recent epidemic of mad cow disease called Bovine Spongiform Encephalopathy and its transmission to the British public by eating tainted beef, led to an investigation. The epidemic was traced to diseased sheep offal including brain that was ground into meal and used as feed for cattle. The unrestrained greed of capitalism and free markets without regulations and supervision becomes a conspiracy to harm or defraud the public as remarked even by Adam Smith, the father of capitalism.

It was Prusiner's pioneering work that showed that the infectious material that transmitted the Prion diseases did so after irradiation, denaturation, boiling etc and may be a protein and not a nucleic acid. So far no nucleic acid material has been shown to be present in the infectious material. Furthermore it is now shown that a gene present in us makes the identical protein found in infectious Prion material. In some instances the amino-acid composition of the genetic and Prion protein are identical but their structure as visualized by X-Ray diffraction etc. is different.

Proteins are a chain of amino-acids with bonding by the CO-NH links. The protein spontaneously assumes a tertiary three dimensional structure depending on the charges on its constituent amino-acids, their hydrophilic or hydrophobic structure and other covalent and or ionic bonds formed with neighboring atoms. The normal protein has alpha helixes and the Prion protein though in some cases identical has beta helixes and seems to change the configuration of the normal protein to its abnormal form by serving as a template. The abnormal protein is insoluble, precipitates, accumulates and is toxic and leads to cell death. Different Prion proteins have a predilection for proteins of specific cell types and parts of the brain and thus cause distinctive symptoms. Here is another case of two identical chemical structures and order of atoms results in different tertiary structures, one of which is healthy and the other leads to fatal disease. Prions are a form of protein isomers in the sense that they have identical composition and structural order but different configurations in three dimensions.

15-Jan-2005
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