Mood, Inflammation, Heart disease, Oxidative stress, Ageing, Cancer and the connection with your gene variants (SNPs) influencing four of the most significant “biochemical cycles” affecting your health – The relationships between the Folate, Methylation, Biopheterin cycles and the Transsulforination Pathway.-
In this “DNA AGE”, literary, DNA is becoming one of the new frontiers and “exploratory new knowledge” of global businesses. From “Body Hackers” in Silicon Valley, to “Internet Giants” – everyone wants to understand how our gene variants (SNPs) connect to our modern lives-.
These “one or two letters” differences in your DNA code can make us “similar to one another” yet “unique.”
Detrimental SNPs can contribute to issues such as :
• the obesity epidemic
• the opioid epidemic and addictions
• alcohol addiction
Recently, Google’s Alphabet new health subsidiary Verily Life Sciences has invested in the quest of analysing complex DNA variants (SNPs) based on their research and clinical studies (1,2).
Alphabet CFO Ruth Porat recently endorsed the initiative based on her struggle with cancer. She went on, saying “Google is finding the most success when it brings medical professionals and technologists together” (2).
On a different front, facebook founder Mark Zuckerberg is financing with a grant of 68 billion dollars a global initiative to map every cell type in the human body (collectively called Human Cell Atlas (HCA) (3).
Indeed, You might have come across yourself, reading recent news on the internet and mainstream media, heralding new “gene codes” like “MTHFR” or “COMT” as a breakthrough in medicine (4, 5, 6, 7).
These and several other gene variants (SNPs) are crucial for their health relevance in a multitude of topics and conditions (4, 5, 6).
However, how these gene variants (SNPs) are “connected” is not a simple matter.
In this article, we will discover, with simple analogies and using descriptive terms, how these genes work together in your complex biological machine.
If you think of your body’s collection of biological and cellular processes as “a molecular clockwork”, each of the “gear wheels” of this clock must move at the right speed to function.
These wheels “rotate” together (i.e. like interlocking wheel dents). If one or more of these wheels does not work correctly, they can potentially stop or cause the clock to malfunction!
Ground-breaking research in recent years has identified some of the “most significant wheels” of this molecular mechanism.
Scientists have also discovered some of the most critical gene variants (SNPs) that are the essential “dents” of these wheels (e.g. MTHFR, MTR, MTRR, COMT, MAT1, ACHY, CBS, BHMT).
The “Folate Cycle” is the central “master wheel” of the body that uses dietary folates to provide the building blocks for DNA synthesis (11).
The Folate Cycle also provides an essential signalling “methyl group”, a vital “molecular tail” that it is attached to molecules involved in numerous other processes including:
• DNA Methylation (i.e. Methyl tails are added to the DNA to switch genes “On” and “Off”). Too low level of methyl group “tails” present on the DNA is called “hypomethylation“. This state contributes to defective gene expression and the ageing process (8,10,11). Too high level of methyl group “tails” present on the DNA causes “gene silencing” which helps several cancers to develop, and for some genes, also contributes to aging (8,10). Scientists also discovered that both people 100 years old or over and newborns have “hypomethylation“ (9).
• Lowering stress levels (9)
• Regulation of inflammation and energy production (10)
• Balancing Neurotransmitters (10)
• Removing toxins (10)
• Improving immunity
HOW DOES THE FOLATE CYCLE -THE CENTRAL MASTER WHEEL- CONNECT TO THE ESSENTIAL “PIECES” OF YOUR MOLECULAR CLOCKWORK?
The Folate Cycle interconnects to three other essential “wheels” of your molecular clockwork:
• The “Biopeterin Cycle”
• The “Methylation Cycle”
• The “Transsulfuration Pathway”
The Folate cycle uses three crucial “dents” of its “wheel” to regulate the interactions with the three Cycle/Pathways mentioned above –these are genes DHFR, MTHFR and MTR/MTRR. –
The DHFR and MTHFR gene connects the folate cycle to both :
• The “Biopeterin Cycle”
• The “Methylation Cycle”
With the Biopeterin Cycle, these two enzymes work together to assist the body to make available a cofactor called Tetrahydrobiopterin (BH4).
Tetrahydrobiopterin (BH4) is vital for :
• Formation of a potent signal molecule called Nitric Oxide (NO) that regulates blood pressure modulate vascular & airway tone, inflammation, insulin secretion and it is involved in angiogenesis (i.e. new blood vessels formation used in wound healing but also during the progression of cancer) and neural development (12,13)
• Assisting as a cofactor specific enzymes during the “transformation” of the amino acid Tryptophan and Tyrosine into two vital neurotransmitters required for mental health: Seratonin and Dopamine. BH4 is also involved in the production of the “fight and flight” hormone “Adrenalin” (13).
DHFR and MTHFR use two different strategies to make BH4 available :
• DHFR “recycle” a “more oxidised form” of BH4 called BH2 by assisting the conversion of BH2 into BH4 by a “reduction process” (13).
• On the other hand, MTHFR prevents oxidation of BH4 into BH2 helping a class of enzymes called “NOS” that are also involved in countering the conversion of BH4 into BH2 (14,15)
• When NOS are not functioning in your body as they should, high BH2 levels leads to the dangerous free radical formation of superoxides (S0)
• Super oxides (SO) significantly contribute to health conditions and speed up the aging process.
On the other hand, with the “Methylation Cycle” DHFR and MTHFR sequentially work together with the same strategy in conjunction with the “third dent” of the folate cycle “wheel” – the MTR/MTRR genes-.
DHFR converts folic acid (from diet and supplements) working together with other enzymes of the Folate cycle, into a form of Folate called “methylene-THF”.
At this point, MTHFR using vitamin B2 is crucial to transform “methylene-THF” into a molecule called “5-L-MTHF.”
“5-L-MTHF” is the popular form of bioactive Folate that mainstream media like to report due to its beneficial effects in treating genetic deficiencies, abnormalities, depression, and many other conditions. (16).
Most dietary Folate transforms into your digestive system, into 5-L-MTHF before entering your bloodstream for utilisation in different tissues (17).
5-L-MTHF is an excellent “methyl- tail donor” that is used by the MTR/MTRR enzymes in combination with Vitamin B12 to convert and recycle Homocysteine into Methionine – two of the pillar molecules in the Methylation Cycle.-
The 5-L-MTHF’s “METHYL TAIL” IS SO IMPORTANT FOR THE METHYLATION CYCLE AND YOUR HEALTH. WHY?
The 5-L-MTHF’s methyl tail donor introduced above, assists during the formation of amino acid Methionine.
MTR/MTRR enzymes reattach the methyl tail taken from 5-L-MTHFR to Homocysteine during its recycling process, creating Methionine.
This methyl tail is then “passed on” from Methionine and “reattached” again to other molecules in a series of additional enzymatic steps.
This sequential process of passing on this “molecular tail” to different compounds during the methylation cycle is essential to your health, and it is vital to biochemical processes including :
• SAMe & SAH formation (10).
• Regulation of hormone & neurotransmitters (10,19,20).
• Epigenetic changes of your DNA (e.g. “hypomethylation“, “hypermethylation as previously described).
WHY METHIONINE and SAMe are CRUCIAL TO DEPRESSION, ANXIETY AND YOUR MENTAL HEALTH?
Methionine generated during the “homocysteine recycling” initial steps of the methylation cycle is “transformed” further by an enzyme called “MAT” to make SAMe. (18)
SAMe are molecules that are also “methyl tail donor” that an important enzyme called “COMT“ “attaches” to neurotransmitters such as Dopamine, Epinephrine and Seratonin to deactivate them (19).
COMT regulates the balance of these brain signal molecules (19).
If there is an imbalance between activated and deactivated neuro mediators (e.g. Dopamine and Serotonin), one can develop depression, anxiety and other psychiatric conditions (20).
COMT, a PHASE II enzyme described in another article on this blog (Detoxification & Inflammation ), links the Methylation cycle to the degradation of neurotransmitters and hormones.
COMT also participates in the metabolism of Estrogen (18).
Women with a genetic makeup that produce a higher level of Estrogen (e.g. women with endometriosis) are at higher risk to develop anxiety and depression.
High levels of Estrogen and low levels of SAMe slows down COMT during its role in the degradation of Dopamine and Seratonin (18). The resulting significant higher imbalance of these two molecules contributes to depression, anxiety and potential mental issues (20, 21).
There is extensive scientific research also confirming that SAMe is useful in the treatment of existing depression, Arthritis and liver disease and other conditions (22).
WHY THE BALANCE OF “HOMOCYSTEINE” IS A CRUCIAL ELEMENT OF YOUR MOLECULAR CLOCKWORK FOR OPTIMAL HEALTH.
Homocysteine (Hcys) is a vital molecule regulated by the Folate and Methylation cycle required for numerous processes.
Homocysteine levels are crucial for optimal health.
High levels of Homocysteine (in medical terms, this is called Hyperhomocysteinemia ) can cause havoc in the body.
Deficiencies of B6, Folic acid (B9), Cobalamin (B12), genetic defects (we will cover these genes (SNPs) further below), moderate and chronic alcohol consumption can raise Homocysteine and contribute to:
• Cardiovascular disease, Atherosclerosis and Thrombosis (23,24,25,26).
• Degradation and inhibition of vital structural components such as Collagen and Elastin present in your skin and arteries! (24).
• Inflammation & Rheumatoid Arthritis (25).
• Dementia (27), Alzheimer’s disease (28,29), Mild cognitive impairment (30).
Recently scientists that study the effect caused by our genes on our psychology, behaviour and mental disorders, connected the impact on high Homocysteine levels to disease.
Research has connected high levels of Homocysteine to the simultaneous rise of the metabolic syndrome and mental illness that “plagues the western population” (31).
Key symptoms of the metabolic syndromes are :
• Low levels of HDL or “good cholesterol carrying molecules” (a sign of diabetes).
• High fasting glucose (a sign of diabetes).
• Diagnosed type 2 diabetes.
• Abdominal Obesity (a sign of diabetes).
WHY “HOMOCYSTEINE BALANCED LEVELS” ARE A KEY COMPONENT FOR ANTIOXIDANT FORMATION, AND FREE RADICAL “CLEARANCE”.
Homocysteine levels must be moderate for the body to function normally.
The body mostly uses ‘two main wheels” of its biological clockwork to ensure that Homocysteine is processed further to avoid high toxic levels:
• Remethylation. In an individual with healthy metabolism, this “recycling process” clears more than 50% of Homocysteine into Methionine employing the “methylation cycle” discussed above (32).
• Most of the remaining Homocysteine converts into the master antioxidant Glutathione using a series of enzymatic processes that scientists call “The “Transsulfuration Pathway” – the fourth essential wheel- (that we introduced earlier in this article).
Several genetic variants (SNPs) must work sequentially like in a “convey belt of an industrial process” to transform Homocysteine (Hcys) first into Cysteine, than into Glutathione.
This process sequentially proceeds as follows:
• Gene/enzyme CBS requires Vit B6, Serine and SAMe to produce an intermediate (41). One other enzyme called CTH/CSE then uses this intermediate to further process and transform it into a new molecule called Cysteine (41).
• Cysteine and Glutamate (i.e. Glutamate is one of the vital substances involved in neural functions) are used by the GCL enzyme to make another intermediate that it is finally converted into Glutathione by an enzyme called GSH (42).
Mutations occurring in some gene variants (SNPs) for CBS, CTH/CSE, GSL, GSH together with lack of Vit B6 and SAMe can disrupt this “molecular convey belt” with detrimental repercussions:
1. If the “convey belt” stops or slows down, high levels of Homocysteine start to “build up” leading to an increase of reactive oxygen reactive species (ROS) that are dangerous to your health (33). Furthermore, this build-up of Homocysteine can also act as an inhibitor to SOD and GPX1 (33). These are two vital enzymes that fight free radicals (also see Detoxification & Inflammation for further insight). SOD and GPX1 convert superoxides and other dangerous free radicals in less toxic compounds like hydrogen peroxide and harmless water (33).
2. Also, If this sequential reaction process is compromised, Glutathione availability drops to harmful levels. Glutathione is the “free radical fighter” involved in oxidative stress.
Glutathione has an influential dual role :
• It forms intracellularly in an area called “cytosol”. It is then actively relocated by the body in the mitochondria of most cells (the energy-producing furnaces of your body ). It acts as a free radical scavenger against some “dangerous molecules” including by-product of our metabolism and external stressors.
• It is also vital during a process called “Phase II conjugation”(also see blog article Detoxification & Inflammation for further insight) that disable harmful molecules like drugs, food additives, and environmental pollutants (34,35)
• During PHASE II, specific enzymes attach Glutathione as a “molecular tails” to these harmful compounds. This transformation makes these molecules water-soluble for excretion via the bile and kidneys and subsequently trough feces /stools and urine.
• Research showed that Glutathione working together with these enzymes helps to prevent and fight conditions such as inflammation (35, 36), Alzheimer’s (37) and many more!
GENE VARIANTS (SNPs) OF YOUR “FOUR ESSENTIAL MOLECULAR WHEELS” CAN DISRUPT THE PROPER FUNCTIONING OF YOUR “BIOLOGICAL CLOCKWORK” CONTRIBUTING TO A MULTITUDE OF HEALTH PROBLEMS AND CONDITIONS.
We covered previously in this article how some of the most critical gene variants (SNPs) are the significant “dents” of the “four essential wheels”.
These “dents” are vital for the correct functioning of your “molecular clock”.
However, what happens to your body when mutations inherited by your maternal or paternal DNA compromise the work of these essential genes?
This question does not lead to a “straight easy answer”; indeed, it gets complicated.
Fortunately, with the fast advancement of science, “new answers” are available. Ground-breaking “large scale” gene studies called Gene Wide Associated Studies (GWAS) that involve large population samples are shedding light on these “genetic anomalies”.
These experiments link gene variants (SNPs) to a large number of conditions (38) such as depression, diabetes, Alzheimer’s, inflammatory disorders and the list goes on.
Investigators have found that if several gene variants (SNPs) concomitantly show adverse mutations, then the health repercussions can be severe.
In simple terms, If multiple dents are “faulty”, on one or more “wheels”, it is likely that the speed and the correct movement of your complex biochemical mechanism deteriorates.
Global research effects are currently investigating some severe mutations and their impact on your health. Some well-investigated facts follow below:
• Genetic defects affect the Folate and Methylation cycles. These are some of the most “popular” and well-described mutations by scientific literature that cause Homocysteine levels to become high and toxic. These “anomalies” compromise the routine processing of 5-L- methyltetrahydrofolate (5-L-MTHF ) that leads to the formation of Methionine, SAMe and Glutathione.
• We have learnt previously in this article that the gene/enzyme MTHFR provides the necessary 5-L-MTHF to two other enzymes MTR/MTRR to recycle Homocysteine into Methionine.
• 10% of the world’s population has more than one form of the MTHFR and MTR genes. Having multiple “types” of the same gene in science is called “polymorphism“. Sometimes genetic polymorphism can be detrimental, resulting in unexpected mutations at specific locations on the chromosomes.
• For example, adverse mutations in gene variants MTHFR 677, MTHFR 1298, MTR 275 may contribute to high homocysteine levels and conditions such as cardiovascular disease, mental health disorders, inflammation and a specific type of cancers (4,5,6).
• Other essential “dents” of “the four main wheels” such as gene variants (SNPs) DHFR, MAT1, COMT, DNMT, ACHY, PEMT, CBS, CTH CSE (6,7, 40) can all feature detrimental mutations depending on the individuals and exacerbate health conditions or make them chronic.
• Furthermore, the situation gets worst if molecules like Vit B2, B6, B9, B12, Betaine, Choline assisting the Folate, Methylation, Biopheterincycle and Trans-sulfuration pathway are Insufficientfrom your diet.
• Fortunately, the “good bacteria” in the gut can make for us a wide range of Vitamins, Betaine, BH4 and many other molecules (39).
• However, there is a catch: poor diet, lack of prebiotics, harmful bacteria and viruses slow down our “good bacteria workers.”
We recommend using a comprehensive DNA testing system in conjunction with expert advice, to discover the list of “strengths” and “weakness” in your DNA to achieve better health.
Your essential “dents” and clock can be “repaired and optimised” with the appropriate exercise, lifestyle, dietary changes.
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