Coenzyme-A Technologies, Inc.TM The Structural and Biochemical Functions of Coenzyme-ATM Nutraceutical product versus the Synthetic compound Coenzyme-A

by Nickolaos D. Skouras, PhD.

Introduction

The nutritional requirements of the human body can rarely be met through a well balanced diet; dietary supplements, including vitamins and minerals are often required to sustain good or optimum health.

Coenzyme-A Technologies Inc.has applied new technology to the formulation and manufacture of a series of proprietary products, which address nutritional deficiencies that result from:

The stress of modern day living, chemical imbalances within the body, pesticides (biologically persistent and ubiquitous toxins) including certain prescription medications and the effects of aging.

These nutraceutical products are the first to provide the human body with a balanced combination of highly active nutritional components and substrates (Chemically bonded) that can be used by the body to support the synthesis and utilization of Coenzyme-A the metabolic enzyme. In addition, certain products also contain their own set of specific substances and nutrient/ substrates that support Coenzyme-A correction or alleviation of particular conditions associated with certain nutritional deficiencies and clinical impairments. It's important to know Coenzyme-A Technologies, Inc. scientific rationale in reference to its product the Coenzyme-ATM a dietary supplement.

Bioavailability, distribution, metabolism and geochemistry of CoenzymeA

Approximately 99% of the dietary /nutraceutical supplement Coenzyme A, is chemically bonded to an intermediate byproduct in the endogenous biosynthesis of the molecule Coenzyme A.  Upon ingestion, where it is absorbed within the intestinal lumen, it primarily undergoes hydrolysis via the formation of Pantetheine and dephosphopantetheine there within the intestinal cells.  Initiated readily by both sodium-dependent active transport mechanism and by passive diffusion. After absorption it is transported to body tissues via the blood, primarily as bound forms in erythrocytes.  Maximum plasma response after oral ingestion was observed 2-4.5 hours followed by rapid declining in concentrations.  Analysis of Pantothenate, usually in the form of CoA- containing species (eg, acetyl CoA, Succinyl CoA) content of rat tissues in clinical studies showed high concentrations in the areas of the heart, kidneys and the liver.

Endogenous synthesis of both CoA and ACP begins within the cells as it undergoes Phosphorylation reactions.   This is the first and apparently a rate- limiting, biosynthetic enzymatic process where it is catalyzed by the Pantothenate Kinase enzyme.  This is a magnesium-depended enzyme, resulting in the formation of Pantetheine 4’- Phosphate or (4-PP) an intermediate product in the endogenous biosynthesis of Coenzyme A.  This is a primary, regulatory point of CoA synthesis, which then is unfortunately inhibited by the end products (high levels of CoA).  This inhibitory action under experimental conditions in rat hearts has been reversed and bypassed with the addition of certain nutrient/ substrates as found in our formula.  Although degradative enzymes exist for the breakdown of CoA, the scattered location of these enzymes within the cell appear to indicate that the cell is geared to minimize degradation of CoA once it has been formed within.  Coenzyme A is formed by the sequential transfer of Adenosine 5’-Monophosphate and modified by a 3’- hydroxyl phosphate.  4’Phosphopantetheine is also found linked to various proteins, particularly those involved in fatty acid metabolism (Plesofsky- Vig, 1999).  The ultimate site for CoA synthesis is assumed to be the mitochondrion as the majority of CoA (which normally does not cross the mitochondrial membrane) is found within these organelles.  In addition to linkage to Diphospho-Adenosine in CoA, 4’-Phosphopantetheine can also be covalently linked to amino acids in a number of cellular proteins. 

With the addition of certain (nutrient/substrates) to our formula the requirements for the transport of activated acyls, namely acyl- Co-As, across the inner mitochondrial membrane have been satisfied.   Fatty acids are found in free form in the cytoplasm and needed to be transported across the inner mitochondrial membrane in a controlled fashion. 

The activated fatty acid is first transferred by a mitochondrial outer membrane protein Carnitine Acyl Transferase I (1) complex from acyl-Co-A to acyl-Carnitine.  The later is than transported across the inner membrane into the matrix compartment by Carnitine Acyl Translocase.  There the fatty acids are reesterfied with a Co-A unit by the matrix enzyme complex Carnitine Acyl Transferase II.

The above are the intricate interactions with Coenzyme A, in which they exert a primary role with any Co-A- depended process and transport mechanisms involved in the mitochondrial metabolism.  These substrates are further catalyzed by several acyl Transferases, which generally are classified on the bases of their affinity for acyl CoA.

An increase in Co-ASH availability or a decrease in acyl- Co-A levels expands the roles of these (nutrient/ substrates) to different choices, including the removal of inhibitory metabolites and the modulation of key enzymatic processes.  In addition some of the nutrient esters appear to specifically modify cellular metabolism, structure and function in order to accommodate certain metabolic conditions.

Beta Oxidation of Fatty Acids

The process of Beta-Oxidation is named after the carbon atom in the beta position of the fatty acyl-Co-A, which becomes the most oxidized during the cyclic redox reactions that move C 2 units in form of acetyl-Co-A from the fatty acyl chain. The beta carbon becomes the new carboxyl end of the shortened(N- fatty acyl-Co-A.

These oxidation steps are strictly analogous to the reaction steps in the Citric Acid Cycle converting Succinyl-Co-A to Oxaloacetate involving an initial oxidation by Acyl Co-A Dehydrogenase enzyme (driven by FAD. Reduction) and hydration by Enol-Co-A Hydratase. The second oxidation is initiated by that is driven by the NAD reduction.

A C2 unit is then released by the Beta-Ketothiolase enzyme to produce acetyl Co-A and a shortened acyl (N2)-Co-A.  The later is recycled until the acyl chain is shortened to its acetyl-Co-A end product and finally oxidized by the Citric Acid Cycle Enzymes.

The structure of the molecule Coenzyme-A

The structure of Coenzyme A or (CoA) includes a reactive thiol group (-SH) that is critical to its role as an (acyl carrier) in a number of metabolic reactions as are mentioned above.  Acyl groups like the acyl molecules from Pyruvic acid become Co-valently linked to this thiol group, forming thioesters.  Thioesters have a relatively high free energy of hydrolysis, thus they have a high acyl group transfer potential, donating their acyl groups to a variety of acceptor molecules.  The acyl group attached to Coenzyme A is considered as activated for group transfer.  Coenzyme A contains Beta- Mercaptoethylamine with the reactive (thiol group), the vitamin Pantothenic acid and the nucleotide derivative 3- Phosphoadenosine Diphosphate.

In almost all cases, the Thiolate form is reactive.  This includes nucleophilic and metal binding (Ionic) reactions. Inactivated thiols have (pKa)- values0f~9. 

A free thiol is in a reduced state; the formation of a disulfide bond is 2e- oxidation.  Disulfide exchange reactions are representative of the redox involvement of thiol cofactors. 

Synthetic forms of Coenzyme and radiolabeled chemical compounds

The efficient microscale synthesis of [1-14C] propional –CoA from commercially available sodium [-14] propionate using 1,1’ carbonyldiimidazole in yields of nearly 70% has been reported recently for the first time.  A substantial improvement in the process for making [1- 14 C] acetyl CoA from sodium [1- 14C] acetate was also achieved.  Reported were yields of greater than 90% were consistently obtained for the later synthesis.  The salt free CoA thioesters were obtained in homogenous form by reverse– phase HPLC.  The products were judged to be pure by 1HMR analysis; neither iso- CoA analogs nor contaminants frequently found in commercial samples could be detected.  The samples of Acetyl- and Propional- CoA were shown to be radiochemically pure by HPLC and analysis of the products of incubations with Acetyl- and Propionyl –CoA Carboxylase.  This highly efficient synthesis being a very cost  effective method of preparation of radiolabled CoA thioesters and can easily be adapted to future production of any other CoA analogs.  The synthetic forms of acetyl Coenzyme A are available from SIGMA ALDRICH, MORAVEK BIOCHEMICALS, BOEHRINGER- MANNHEIM, and PERKIN ELMER Life Sciences, Inc. just to name a few.   They have been successfully used in their purified form for the synthesis of such pharmaceutical anticancer drugs such as Taxol, and some of the major antibiotics.  . 

Biovailability, distribution and metabolism of the synthetic compounds of CoA

Scientific studies using synthetic chemical compounds of CoA in isolated rat intestine indicated that orally administered CoA was hydrolyzed to Pantothenic acid within the intestinal lumen via the formation of Dephospho- CoA , Phosphopantetheine and Pantetheine to Pantethine and finally Pantothenic Acid, but not the actual CoA molecule (Shibata et al., 1983).  Pantetheinase, an enzyme which can hydrolyze Pantetheine and Pantethine, has been identified in rat intestinal luminal cells (Ono et al., 1974; Shibata et al., 1983; Wittwer et al., 1985).  Pantetheine, formed by the stepwise breakdown of CoA, is hydrolyzed to cystamine and Pantothenate, which is excreted in the urine (Whittwer et al., 1983).  Although Pantothenic Acid may be absorbed by passive diffusion (the predominant process at high intraluminal Pantothenate concentrations), a saturable, sodium -depended, active transport mechanism has also been described (Fenstermacher & Rose, 1986; Stein & Diamonds, 1989).  Further studies indicated that the kinetics of this active intestinal transport process for Pantothenate were not affected by different dietary intake levels of the vitamin form (Stein & Diamonds, 1989). 

The above radiolabeled synthetic compounds had the following warnings: Caution: not for use in humans or clinical diagnosis.  These products were intended for investigational, testing purposes, or for manufacturing use only.  They are pharmaceutically unrefined and not intended for use in humans.  Further stability and storage recommendations were: rate of decomposition is approximately 0.1-0 to.0 5% month for the first six months after purification when stored at –20*C.

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