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Enzymopathy as a result of Polymorphism By M. Nicholas Martin MD/ABARM Definitions: Enzymopathy: A pathological process that fails to produce the normal enzymatic product from an available substrate. An enzymopathy can be a result of single nucleotide polymorphism (SNP) that creates an enzyme that is a) repetitive, requiring additional cofactors to be present or b) enzymes are disabled, as a result of abnormal amino acid sequence or c) a failure of an enzyme to activate a cofactor.. Repetitive Enzymes In their normal forms, enzymes facilitate the conversion of substrate biochemicals to a product. However, most chemical reactions require cofactors that interact with the enzymes to complete Figure 1. NORMAL ENZYMATIC REACTIONS (Showing the mechanism of Enzyme Cofactor intersection) Substrate ^!^!^!^!^!^!^!^ Product !=enzyme ^=cofactor these chemical reactions thus forming products. (see Figure 1.) The products can be new cofactors, hormones or other products. When polymorphisms occur, the DNA process is repeated requiring the cofactor/enzyme process to be repeated multiple times in order for adequate products to be produced as shown in figure 2. As a result, a significant increase in enzymatic cofactors is required. Figure 2. ABNORMAL ENZYMATIC REACTIONS NEEDING EXCESS COFACTORS Substrate ^!^!^!^!^!^!^!^ ^!^!^!^!^!^!^!^^!^!^!^!^!^!^!^Product !=enzyme ^=cofactor Disabled Enzymes Enzymes may also be disabled as a result of polymorphisms. When polymorphic amino acid sequences are present in the enzymes, the enzymes are inadequate for transfer of the biochemical unit to a product. In essence, the enzyme is disabled and therefore cannot facilitate product production. Failure of an Enzyme to Activate a Cofactor Polymorphisms can not only disrupt product production but can also disrupt the processes necessary to produce or activate cofactors—ultimately leading to the disruption of product production. One example is the production of the activated cofactor Riboflavin— 5—phosphate (R-5-P). Figure 3 depicts this process. Riboflavin combines with thiamine benfotiamine to produce Ribflavin—5—phospate, an activated cofactor. Pyridoxal HCL then combines with R5P to produce another activated cofactor, pyridoxal—5– phosphate. If there are not enough cofactors available, inadequate product is produced. In this example, P-5-P may not be produced in adequate quantities to facilitate other biochemical processes needed by the body (Figure 4). Figure 3. Thiamine Benfotiamine (TB) (cofactor) Riboflavin TB TB TB TB TB TB Riboflavin-5-Phosphate (R-5-P) (substrate) (Product) Phosphatase Enzyme Activated Cofactor producing an Activated Cofactor (R-5-P) Riboflavin-5-Phosphate (R-5-P) (cofactor) R-5-P R-5-P R-5-P R-5-P R-5-P R-5-P Pyridoxal Pyridoxal-5-Phosphate (P-5-P) (substrate) (Product) Phosphatase Enzyme Normal Enzyme with Activated Cofactor producing another Activated Cofactor (P-5-P) Figure 4. Enzymopathy Treated with Normal but Limited Cofactor (R-5-P) Pyridoxal HCL R-5-P R-5-P R-5-P (substrate) No Product Produced Phosphatase Enzyme (Repeats – demanding higher levels of R-5-P) Lack of P-5-P Production is a Sign of Deficient R-5-P Cofactor Steroids and Polymorphisms Steroids are required in adequate quantities for the activation of genes necessary to produce the needed enzymatic proteins. If steroids are not available, the enzymes necessary to produce biochemical products will not be available and the products will not be made. Hormonal steroids include testosterone, DHT, estrogens, HGH, chorionic gonadotropin, and thyroid hormones. Additionally, some (vitamin steroids), although not of the glandular hormones grouping, act as hormones in the process of gene activation and help to activate the receptors of some of the glandular hormones. These include vitamin D (many subcategories), vitamin A (many subcategories), vitamine E (Gamma/Delta), vitamin K2 and osteocalcin. Problems Related to Enzymopathies In order to understand the problems associated with enzymopathies, one must keep in mind that the human body is a complex web of biochemical processes. As a result, a deficiency in a cofactor or enzyme may lead to a deficiency in another cofactor that is required to make the original cofactor. As an example, Vitamin D is needed to make enzymes that are necessary to make P-5-P which in-turn is a cofactor for making Vitamin D. Therefore, when a certain enzymopathy is uncorrected, it can contribute to a cascade of negative biochemical reactions that can leave the body deficient of one or more products necessary for optimal homeostasis. P-5-P and R-5-P Deficiencies Leading to Examples of Product Deficiencies Since enzymopathies often require significant cofactor quantities not required with normal enzymatic reactions, cofactor levels are often inadequate. R-5-P and P-5-P are cofactors that are often deficient when enzymopathies are present. Having insufficient levels of P-5-P or R-5-P often leads to deficiencies in vitamin A, vitamin D, niacin and coenzyme Q-10. Furthermore, if these cofactor levels are low, the neurological chemicals serotonin, norepinephrine and dopamine may be deficient. Low levels of P-5-P or R-5-P can also result in the ineffective formation and metabolism of hormonal steroids. Both cofactors play significant roles in the Kreb’s cycle. Without them, ATP is underproduced and mitochondria functions are hampered. Without the vitamin, neurological components and hormonal steroid products, there is a significant mitochondrial energy loss. The catabolic steroid cortisone and the immediate survival hormones norepinephrine and epinephrine all are released and become chronically elevated as a result of autonomic nervous system reactions to the cofactor deficiency. The lack of proper cofactor functions and product formation results in the perception by the body of critical failure of available nutrition ( biochemicals needed for function and to produce energy). This results in cortisone formation which in-turn releases the byproducts of the stress induced energy (sugar acetylcoA) formation to meet the mitochondrial energy needs. In certain genetic– polymorphism populations, multiple deficiencies resulting in chronic cortisol elevation will rapidly age as they chronically and metamorphically change to a pre-cushionoid state. Metabolic Syndrome Metabolic syndrome is defined as “A syndrome caused by one or more single nucleotide polymorphisms that alter the metabolic pathways in pathological ways with resultant classical diseases”. The Glucocorticoid Receptor (GR) has been found to have mutations in the GR alleles that likely correspond to polymorphisms caused by SNPS that have been associated with metabolic syndrome. As a result of the polymophisms, enzymopathies are prevalent requiring increased cofactors above normal levels. One example of this enzymatic need for increased cofators is the finding that patients with elevated cortisol, secondary to elevated cortisol receptors, can ingest P-5-P at a level of 300 mg (approximately 75 times the recommended dose of P-5-P) and suppress cortisol by blocking the formation of cortisol. ?????Does the high dose P5P correct the GR mutation thus decreasing cortisol levels. The umbrella of metabolic syndrome diseases include: diabetes mellitus, hypertension, hyperlipidemia, early kidney disease(proteinuria), visceral obesity, chronic inflammation, and proliferative tumors or cancers including breast cysts, polycystic ovarian disease and polyps (colon/skin/vaginal). ??cervical or vaginal???? Immune Deficiency of Cancers, Recurrent and Chronic Infection Polymorphisms and enzymopathies also play a significant role in the immune system thus requiring significant cofactors. The immune deficiency of cancer, recurrent and chronic infection is often caused by a deficiency of cofactor or steroid cofactor, or a combined deficiency of both. The vitamins and vitamin steroids that are most likely deficient in immune deficiency are a) zinc b) Vitamin A c) Vitamin C d) Vitamin D e) P-5-P f) Riboflavin-5-Phosphate, g) selenium. Do we need a sentence here that ties the following paragraph into immune deficiencies???Allergic conditions that have exemplified enzymopathies include allergic rhinitis, food allergies, environmental allergies and contact dermatitis. Inflammatory diseases include rheumatoid diseases, scleroderma, ulcerative colitis with arthritis, regional enteritis with arthritis and polymyositis. Diagnosis of Enzymopathy 1. Interleukins Effect 2. Vitamin A 3. Vitamin D 4. Serotonin 5. Catecholamines (epinephrine, norepinephrine, and dopamine) 6. Vitamin B6 (activated not differentiated from inactive) 7. Vitamin B2 (activated not differentiated from inactive) 8. Parathyroid Hormone In addition to the initial lab screening, ineffective enzymes can be identified clinically. Signs of faulty metabolism include: a. Metabolic Syndrome b. Deficiency of products of enzymatic reaction (see initial screening above) c. Elevation of vitamin/cofactors without history of excessive intake d. Elevated levels of inactive cofactors are lowered in response to activated cofactor treatments e. Laboratory findings of products of enzymatic reactions being deficient, or elevated. Example: Serotonin is increased due to the deficiency of the enzyme that breaks it down or catabolizes it. Serotonin is low if the enzyme that forms it is defective or the enzyme that breaks it down is extremely efficient thus removing serotonin faster than it can be formed. Treatment Protocols Vitamin Steroid Deficiencies Usually, more than one steroid is required to activate the protein synthesis needed for enzyme formation. A combination of vitamin steroids and natural glandular steroids is the normal mixture of effective steroids. The most effective steroids for inducing enzyme formation for metabolic syndrome are vitamins (steroid) Vitamin D and osteocalcin. Vitamin A can be formed by multiple enzymes requiring multiple cofactors. One of the enzymes requires P-5-P. Raw materials are carotenoids and cofactor zinc (in large quantities). The intake of carotenoids and P-5-P without zinc results in severe zinc deficiency which can cause a range of illnesses from disorientation to aggressiveness (or minimum irritability behavior) and from severe infection to Sepsis. If a person does not have an enzymopathy, then all that is needed to produce the zinc deficiency is excess beta carotene, which is the driving substrate to form vitamin A when zinc is present therefore zinc is consumed in the formation of vitamin A. Vitamin D can be formed by enzymes cofactored with Riboflavin-5-Phosphate (R-5-P) and Pyradoxal-5-Phosphate (P-5-P). Vitamin D is the most effective vitamin steroid. Osteocalcin can affect the metabolism through enzyme induction. Vitamin K (a steroid vitamin) can stimulate osteocalcin production. Vibrations can also stimulate the release of osteocalcin. Hormonal Steroids Testosterone is the most effective steroid in the induction of formation of effective metabolic enzymes, such as formation of pyridoxal-5-phosphate. Cofactors and enzymes may be chemically effective to drive this reaction. For example, without adequate zinc, beta carotene elevates and zinc becomes depleted toward an undetectable level. Without the cofactor P-5-P, both zinc and beta carotene blood levels will usually elevate above normal. If lack of supplementation of beta carotene, supplementation of zinc will deplete the reserve of beta carotene in the skin. Estradiol must be present in women for adequate cofactor– enzyme functions in regard to induction of enzymes needed for biochemical homeostasis. Hormonal steroids can be improved with cofactors P-5-P and R-5-P. If this is inadequate, bioidentical hormones can be used to reestablish the steroidal induced enzyme formation.