Download Enzymopathy as a result of Polymorphism

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.