Chirality
Mitochondrially targeted nutrients in their naturally occurring, optically active forms
"We eat optically active bread & meat, live in houses, wear clothes, and read books made of optically active cellulose. The proteins that make up our muscles, the glycogen in our liver and blood, the enzymes and hormones... are all optically active. Naturally occurring substances are optically active because the enzymes which bring about their formation... are optically active. As to the origin of the optically active enzymes, we can only speculate." (1)
Chirality (Pronounced Ki-Rality) Defined
The term "chiral" is derived from the Greek word "kheir" meaning hand, the most familiar chiral object, and designates the existence of left/right opposition. For example, your left hand and right hand are not identical and yet are mirror images of each other, and are therefore "chiral".
Just as human hands come as left and right, so do some molecules. A chiral molecule is one that is not superimposable on its mirror image. A chiral compound and its mirror image are called enantiomers. Almost all chiral molecules in nature are present as a single enantiomer. When molecules are produced by industrial synthesis they usually exist in a racemic form, which is a 50/50 composition of the two enantiomers.
Chiral compounds exhibit optical activity, so enantiomers are sometimes called optical isomers. Each enantiomer rotates the plane of 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 (-). A racemic mixture and does not exhibit optical activity.
In 1848, when Louis Pasteur was 26, he used tweezers to separate right- and left-handed forms of tartrate under a microscope. The crystals have a different shape. When Pasteur dissolved the crystals in water, one set rotated polarized light to the right, and the other form rotated it to the left.2 Tartrate was therefore the first molecule ever isolated in right-handed and left-handed forms, which chemists now refer to as the R (from the Latin rectus, for right) and S (from the Latin sinister, for left) forms.* This experiment is usually cited as the discovery of chirality in molecules, although it was almost a hundred years before chemists began using this term.
*R and S are designations for the absolute configuration of the molecule which shows how the atoms are configured around the chiral center, according to priority rules.
Chirality And The Body
A basic premise of orthomolecular medicine, making both logical and intuitive sense, is to feed the body nutrients in their naturally occurring, chiral forms, because the body's receptors are all chiral. They are like gloves that are made to fit only the correct hand. The two enantiomers of any chiral molecule will interact with living systems in different ways.
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.
Other biological receptors are triggered by only one of the two enantiomers of a chiral molecule, often being unresponsive to the other enantiomer, or responding more weakly. For example, S-carvone is the flavor of caraway while R-carvone is the flavor of spearmint. There are many examples of the remarkable differences in pharmaceutical activity of chiral drugs: for example, R-albuterol is an antiasthmatic, the S-form constricts airways.
A single enantiomer will, in the majority of cases, be superior to the racemic mix for a specific function. There are numerous examples from pharmacology where the opposite/unnatural isomer 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
The naturally occurring form of Alpha Lipoic Acid is R-(+)-Lipoic Acid (RLA) and the unnatural form is S-(-)-Lipoic Acid.
The commercially available form is racemic Alpha-Lipoic Acid and is composed of a 50:50 mixture of R-Lipoic acid and S-Lipoic acid.
Racemic ALA has been shown to be therapeutically valuable, but the efficacy may be enhanced with pure R-Lipoic Acid, which has only recently become commercially available. There are no human clinical trials to date comparing racemic ALA and R-Lipoic Acid head to head. There are some significant reports from animal and in vitro studies claiming substantial and significant differences between R-Lipoic Acid and its mirror image SLA in age and disease related functions.
To learn more about these differences see: R-lipoic acid.
Anti-Inflammatory/Antioxidant
R-Lipoic Acid has been shown to be 10 times more effective than the racemate 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
R-Lipoic Acid 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
R-Lipoic Acid increased ATP production in working rat heart whereas SLA inhibited it.5
Proposed Mechanisms Explaining The Differences Between R-Lipoic Acid, SLA And Racemic ALA
These differences implicate the S-isomer as interfering with the cell's ability to maximally utilize the natural R form. We propose that SLA competes with R-Lipoic Acid for cellular and/or mitochondrial membrane transport mechanisms or blocks the ability of R-Lipoic Acid to bind to its enzyme once it crosses the mitochondrial membrane.
SLA is predominantly reduced in the cytoplasm by the NADP(H) dependent glutathione and thioredoxin reductases, and has limited ability to be actively transported into the mitochondria. This suggests that SLA is blocking up membrane channels or interfering with R-Lipoic Acid transport mechanisms in the cytoplasm rather than within the mitochondria.
R-Lipoic Acid 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 R-Lipoic Acid which alters the cellular redox status and 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 2003, one third of all drugs were pure enantiomers overall, and half of the top 100 where chirally pure. The top-10 list for these products includes such familiar brand names as Lipitor, Zocor, Paxil, Zoloft, and Nexium--all of which yield sales of over $1 billion a year.6
References
- Morrison , R.T. and Boyd , R.N. , 1987. Organic Chemistry 5th ed. Allyn & Bacon Inc. p.150.
- L. Pasteur, Two lectures delivered to the Societe Chimique de Paris, Jan. 20 & Feb. 3, 1860.
- 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.
- 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.
- 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.
- Chiral Drugs October 23, 2000 Volume 78, Number 43, Cenear 78 43 pp.55-78.