Monday, May 07, 2007

Chirality: Its cause and importance.

A chiral molecule is one that can exist as a pair of mirror image, non-super imposable enantiomers. This molecule requires a carbon atom that is attached to four different substituents (groups of atoms), the carbon is referred to as the stereogenic or chiral center. Methane (CH4) includes a carbon atom that is covalently bonded to four hydrogens. It contains no stereogenic center; therefore it is achiral. A carbon that is doubly bonded to another carbon (such as in an alkene) or to any atom (such as in ketones) are achiral by virtue of a carbon atom that is sp2 hybridized, the doubly bonded substituent would be counted twice. In ketones a carbon is doubly bonded to an oxygen molecule, this carbon would have at least two of the same substituents and therefore be achiral.

A mirror image, non-super imposable pair of enantiomeric molecules would be similar to a left hand/ right hand comparison. They look exactly the same but their three dimensional stereochemistry does not allow them to be super imposed on each other. Both pairs will have the same density, the same melting point and the same solubility the only difference being the direction to which they rotate polarized light.

Chirality plays a very important role in biological function. Since enantiomers do not have the same biological effect it’s important that the correct one is utilized; whether this is the construction of bio-macromolecules (proteins and nucleic acids) or the use of pharmaceutical drugs.

Dopamine has one stereogenic center; therefore exists in two pairs of enantiomers – levorotatory Dopa (L-Dopa. The ‘L’ signifies the counter clockwise direction that the asymmetrical molecule rotates polarized light) and dextrorotatory Dopa (D-Dopa – rotating polarized light clockwise). One enantiomer has no use biologically and the other fights Parkinson’s disease (L-Dopa). The L-enantiomer is the only stereoisomer that matches the target site’s chiral receptor. Like a ‘key in lock’ fit, the correct enantiomer is necessary in order to deliver the molecules biological benefit.

Historically in drug development and treatment, a racemic mixture of both enantiomers (50/50 mixture) would be used. It was simpler to yield a mixture opposed to just one of the enantiomers. But cases surfaced when the other enantiomer (not specific to the cure) did carry a negative effect. One instance would be the use of thalidomide to treat morning sickness in pregnant women. While the intended enantiomer performed its task, the other lead to deformities in babies.

The role of chirality and handedness in life’s origin is even more important. The incorrect enantiomer in drug design can harm life, the incorrect enantiomer in biological origins can prevent life. In order to obtain chiral molecules via synthesis you need to begin with a chiral starting material. Reactions between achiral reagents yield either racemic products (50/50) or meso-compounds (molecules with a stereogenic center but achiral by virtue of a symmetry plane that cuts through the molecule); neither of which are useful in constructing proteins or nucleic acids. Scientists have attempted to synthesize amino acids with the correct stereochemistry under the conditions that are believed to be similar to those of ancient Earth, but obtaining left-handed (L-enantiomer) dominance has proven elusive.

Even when considering an extraterrestrial source, such as the Murchison meteorite, no complete dominance in left-handed amino acids has been discovered. While some scientists noted a slight left-handed excess others stated that the amino acids were racemic and that any apparent dominance of left-handedness was from terrestrial contamination (Jeff Bada – Scripps Institute, Keith Kvenvolden – NASA Ames). There still exists some disagreement regarding the slight left-handed dominance or non-dominance in the meteorite, as well as over the sample being contaminated or uncontaminated; however, the possibility still remains that this meteorite may tell us nothing. There’s still a distance to travel from slight dominance to the degree of handedness that characterizes terrestrial life.


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