chirility

CHIRALITY

Chirality Defined
The word “chiral” is derived from the Greek word for hand, and designates handedness in molecules (your own left and right hands are made up of the same things, a palm 4 fingers and a thumb, but are not the same configuration and are thus mirror images of each other). When a molecule exists in a chiral form, with a single chiral carbon (center) it exists in two mirror image forms (called enantiomers) which are not superimposible. Life is chiral and almost all chiral molecules in nature are present as a single enantiomer.

*Each enantiomer rotates the plane of plane polarized light in opposite directions, and is therefore called optically active. The enantiomer that rotates light in a clockwise direction is dextro or (+) and the opposite enantiomer is levo or (-). R (the “+” form) and S (the “-” form) are designations for the absolute configuration of the molecule which shows how the atoms are configured around the chiral center, according to priority rules.

The naturally occurring form of Alpha Lipoic Acid is R-(+)-Lipoic Acid and the unnatural form is S-(-)-Lipoic Acid.
The commercially available form is racemic (abbreviated “rac”) Alpha-Lipoic Acid and is composed of a 50:50 mixture of RLA and SLA.)

Therefore it makes both logical and intuitive sense to feed the body nutrients in their naturally occurring, chiral forms. The two enantiomers of any chiral molecule will always interact with living systems in different ways. When molecules are produced by industrial synthesis they exist in a racemic form, which is a 50/50 composition of the two enantiomers.

When the racemic mixture is consumed, the body must determine what to do with the unnatural enantiomer, which may be inert, have a unique physiological profile, antagonize the activity of the opposite enantiomer, or possibly have increased toxicity or teratogenic properties. An extreme example of this principle was the thalidomide tragedy of the 1960’s. One enantiomer prevented morning sickness, whereas the opposite enantiomer caused serious birth defects.
A single enantiomer will, in the majority of cases, be superior to its mirror image for a specific function. There are numerous examples from pharmacology (the study of drug action) where the opposite/unnatural mirror image molecle in some manner inhibits or opposes the function of the desired enantiomer. In the nutraceutical world there are recognized differences between the two enantiomers of vitamin E, amino acids, sugars, vitamins (biotin), prohormones, enzymes, and neurotransmitters.

Chirally Pure R-Lipoic Acid vs racemic Alpha Lipoic Acid
Racemic ALA has been shown to be therapeutically valuable, but the efficacy may be enhanced with pure RLA (+), which has only recently become commercially available. There are no human clinical trials to date comparing rac-ALA and RLA head to head. There are three significant reports from animal and chemical studies claiming substantial and significant differences between RLA and its mirror image SLA in three age and disease related functions.

Anti-inflammatory/Antioxidant
RLA has been shown to be 8-10 times more effective than the mirror image SLA in its anti-inflammatory effect. 2 Inflammation and increased oxidative stress have been implicated in all the chronic degenerative diseases of aging. 3

Pyruvate Dehydrogenase Activity Increased
RLA increases the activity of the crucial mitochondrial PDH enzyme (inhibited by age-related diseases such as diabetes) whereas SLA inhibits it. 4

Increased ATP Production
RLA increased ATP production in working rat hearts whereas SLA inhibited it. 5

Proposed Mechanisms Explaining the Differences Between RLA and Rac-ALA or SLA
These differences implicate the mirror image S-isomer as interfering with the cell’s ability to maximally utilize the natural R form. We propose that SLA competes with RLA for cellular and/or mitochondrial membrane transport mechanisms or blocks the ability of RLA to bind to its enzyme once it crosses the mitochondrial membrane.

SLA is predominantly reduced in the cytoplasm by glutathione reductase, and has limited ability to be actively transported into the mitochondria. This suggests that SLA is blocking up membrane channels or interfering with RLA transport mechanisms in the cytoplasm rather than within the mitochondria. RLA has the ability to both bind preferentially to the PDH enzyme and re-reduce oxidized terminal sulfhydryl residues of key mitochondrial enzymes. Oxidized sulfhydryl groups disturb or completely inhibit enzyme function and are markers of age related oxidative stress. In experimental animals these oxidized sulfur containing amino acids could be re-reduced and re-activated by RLA, altering cellular redox status which regulates gene expression.

The Chiral Future is Now
The race is on in the pharmaceutical and nutraceutical industries for enantiomerically pure compounds. The 2001 Nobel Prize in chemistry was shared by three chemists for their discoveries in asymmetric catalysis which allows a single enantiomer to be produced synthetically. Within 10 years the FDA will only allow single enantiomer drugs and nutrients for human and animal consumption, once the differences between the racemates and the pure enantiomers are completely characterized. In 2000, 35% of drugs were pure enantiomers overall, and 50% of the top 100 where chirally pure. The demand for chiral products has been growing at a rate of 8% per year, and this year sales are expected to reach 146 billion, worldwide. 6

References

1) Morrison, R.T. and Boyd, R.N., 1987. Organic Chemistry 5th ed. Allyn & Bacon Inc. p.150.
2) Ulrich H, Weischer CH, et al. Pharmaceutical composition containing R-alpha-lipoic acid or S-alpha-lipoic acid as active ingredient. US Patent 5,728,735,1998.
3) Life Extension Magazine Collector’s edition 2002 pp 100-108, Chronic Inflammation, The Epidemic Disease of Aging and references cited therein. Life Extension Magazine Sept 2003, pp 24-38, Inflammation and the Aging Brain by Dale Kiefer and references therein.
4) Klaus Wessel, Harald Borde, et al. Use of R-(+)-alpha.-lipoic acid, R-(-)-dihydrolipoic acid and metabolites in the form of the free acid or as salts or esters or amides for the preparation of drugs for the treatment of diabetes mellitus as well as its sequelae. United States Patent 6,117, 889. September 2000.
5) Tory Hagen, Russell Ingersoll, et al. (R)-Lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB 13:411-418, 1999.
6) http://pubs.acs.org/cen/coverstory/7843/7843scit1.html

The products and the claims made about specific products on or through this site have not been evaluated by the United States Food and Drug Administration and are not intended to diagnose, treat, cure or prevent disease. The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information on this site for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem.