Genomics Flashcards
Epigenetics
As an organism grows and develops, carefully orchestrated chemical reactions activate and deactivate parts of the genome at strategic times and in specific locations. Epigenetics is the study of these chemical reactions and the factors that influence them.”
Video on epigenetics
https://www.youtube.com/watch?v=81rFpRsF80c&feature=youtu.be
Intro to Nutrigenomics
Health/Diet (Nutrition in between)
Diet/Genomics (Microarrays, proteomics, metabolomics, epigenomics between)
Genomics/Health (longevity, markers, behvaioral genomics in between)
within all three: (health, diet, genomics) Nutrigenomics
Nutrigenomics vs. Nutrigenetics
Nutritional genomics covers nutrigenomics, which explores the effects of nutrients on the genome, proteome and metabolome,
nutrigenetics, the major goal of which is to elucidate the effect of genetic variation on the interaction between diet and disease.”
If ApoE, may want to suggest dietary changes, however you cannot say it is because of higher risk of Alzheimers. Need to provide supportive literature for docs when sending referral. Need to have a kick-ass disclosure to protect yourself on every level.
Statutory Definition of Nutrigenomics
Nutritional genomics means the consideration of biochemical or genetic information to evaluate how genetics effect gene function and how genetic variation alters nutrient response, including the study of how dietary and other lifestyle choices influence the function of humans at the molecular, cellular, organismal and populational levels.”
Genetics 101/DNA Replication
https://www.facebook.com/AAMB.UK/videos/vb.305735409443436/304240952939950/?type=3
Methylation Basics
what is methylation?
The most common methylated base in humans is 5-methylcytosine.
1.A methyl group is 1 carbon and 3 hydrogens
2.Methylation is the process of adding or subtracting this group from different compounds.
What is the function of methylation?
1. Gene regulation
2. Biotransformation
3. Neurotransmitter synthesis
4. Hormone catabolism (estrogen)
5. DNA and histone synthesis
6. Energy production
7. Build and maintain cell membranes (phosphatidylcholine/serine)
To Add or not to add a methyl donor
-Adding a methyl group or hypermethylation silences gene expression
-Removing a methyl group or hypomethylation activates gene expression.
To silence gene – hyper methylation
To silence, adding in methyl donors.
If heathy, do not want to add methyl donors. Adding donors tells body to stop making DNA, stop transcription. Many supplements are full of methylated micronutrients.
Body should do a good job of methyl donors on it’s own.
Adding them in “shouts” at metabolic pathways. Do not want to add methyl donors in 99% of the time. Methylation only one way to turn on/off genes… many more: Acetylation, etc. Not always methyl donor turning things on/off.
What Negatively Impacts Methylation
- Insufficient cofactors or substrates
- Medications that block absorption (antacids, methotrexate, metformin, etc.)
- High dose niacin depletes methyl groups
- Environmental toxins, heavy metals, and chemical exposure
- Too much substrate causes feedback inhibition
- Genetic mutations
- Mental state
Blocked absorption creates insufficient cofactors and substrates. Too much Vitamin C causes diarrhea – lower doses to actually absorb. Transporters can only handle about 500 mg at a time. Absorption is 98% or so. One dose of 1000mg of Vit C, transporters only handle 50% and the rest is flushed out of the system. Vitamin C is not fat soluble. Vitamin D is, so want a liposomal delivery system. Not for Vitamin C.
What is a SNP?
https://www.youtube.com/watch?v=moQdU7nH-jg
Basics of homocystein metabolism
1.Methionine is methylated homocysteine
2. This is a breakdown product of SAM SAH via AHCY (adenosylhomocysteinase)
3. The only difference is the addition of a methyl group on homocysteine.
4. Methionine = homocysteine + Methyl group
homocysteine metabolism
Dietary Folate/Folic Acid
DHFR/NADPH (DHF > THF)
MTHFD/NADP > 10- Formyl THF
5, 10 Methylene THF>MTHFD1> 10-Formyl THF
5,10 Methylene THF > MTHFR (FAD, NADP),
MTHFR > 5-MTHF> MTR/MTRR (vitamin B12) > Methionine
Betaine > DMG
Methionine uses conversion of Betaine to DMG to make Homocysteine (CBS , B6)> Cystathionine >
Taurine, glutathione, sulfate
BHMT (Zn) is in the conversion with Homocysteine to Methionine
Methylation pathway also recycles B12. Recycles methyl donor to pass off to MTHFR to create methyl donor (methylate folate). Homocysteine can go back to methionine, but not as common as the Glutathione pathway.
Homocysteine catabolism
Three Possible Routes:
MTR/MTRR (50%) – Vitamin B12 and Folate
BHMT – TMG and Zinc
CBS (50%) – Vitamin B6 – Only eliminating route
May use choline/phosphatidylcholine in place of TMG for those with BHMT SNPs that are sensitive to methyl donors as choline is the precursor to betaine.
Betaine may be increased by consumption of beets and Swiss chard.
Not much zinc needed to get methlylation going. Folate interacts, but is not required (first route). CBS Cystationine beta synthase? When client says sensitive to active B vitamins… actually mean methylated.
MTR/MTRR
- Methionine synthase
- Methionine synthase reductase
- Function: Recycles homocysteine back into methionine in order to produce SAM (S-adenosylmethionine)
- SAM: the universal methyl donor
- MTR Cofactor: Zinc, blocked by lead, aluminum and mercury.
- MTRR Cofactors: SAM, FAD, NAD, blocked by lead
Methionine Synthase
(MTR/MTRR)
- Methionine Synthase
- Methionine Synthase Reductase
- Accounts for half of homocysteine catabolism.
- Recycles homocysteine back to methionine.
- IS the connection between one carbon metabolism and methylation.
Methionine>Homocysteine>MTR/MTRR (vitamin B12)> Methionine
BHMT
- Betaine-homocysteine S-methyltransferase
- Cofactor and enzymes: zinc, DMG->TMG via choline, blocked by glucocorticoids.
- Function: Supplies a methyl group to convert
homocysteine back to methionine and betaine to dimethylglycine (DMG) - Betaine + homocysteine → dimethylglycine +
methionine - Mutations may increase homocysteine levels
(theoretically)
How many patients do you have that are Zinc deficient.
Betaine Homocysteine Methyltransferase (BHMT)
- Betaine-Homocysteine S-Methyltransferase
- The short cut through the methylation cycle.
- Supplies a methyl group to convert homocysteine back to methionine and betaine to dimethylglycine (DMG).
CBS overview
- Cystathionine Beta Synthase
- Cofactor: Vitamin B6 (pyridoxal-5-phosphate)
- Function: Converts homocysteine to cystathionine
>Blocked by lead - Product: Hydrogen sulfide (H2S) and cystathionine
- CBS C699T, C1080T, and C1985T variants are fast forward enzymes
- CBS A360A and CBS C9150T variants are slow enzymes.
- Slow or fast CBS mutations may result in autism, down syndrome, connective tissue disease, cancer and homocystinuria.
- (much more on this later)
Cystathionine Beta Synthase
- Cystathionine Beta Synthase
- Accounts for half of homocysteine catabolism
- The only true disposal route
- Converts homocysteine to cystathionine
Case Study : Homocysteine and stress case study
John is a busy executive working 70 hours per week. His symptoms include insomnia, stress and has occasional diarrhea and anxiety.
>You ran an initial four-point adrenal stress index (ASI) which indicated that cortisol is elevated throughout the day.
>A serum homocysteine was also run and was lab high at 16 mmol/L (range is 4-16 mmol/L).
>An organic acids test was also run which includes methylmalonic acid (MMA), formiminoglutamate (FIGLU) and xanthurenate which assess vitamin B12, folate and vitamin B6 status respectively. When elevated these markers indicate a cellular insufficiency. While xanthurenate levels were normal, both MMA and FIGLU were elevated.
>How would you proceed? Are there any SNPs that you would expect to find? Do you think that there is a relationship between stress and homocysteine?
MTR/MTRR
Perhaps MTHFR
Probably block from Homocysteine to cystathionine – B6 deficiency, Probably blocked at Mtr/Mtrr – maybel MTHFR snp. Inflammatory markers not the whole picture.
Stress and methylation
> Talk to me about what you see here.
What is the chemical difference between Epinephrine and Norepinephrine?
What enzymatic process is being catalyzed by PNMT?
What do you think it means for those under chronic stress?
What do you think about their methylation status?
How about their Hcy Levels?
Difference between norepinephrine and Epinephrine is methyl donor – CH3. Stress uses up methyl donors = elevated levels of homocysteine whether system is broken or not.
Simplified Focus on MTHFR- The celebrity SNP
1.URea cycle
2. BH4 Cycle (Tryptophan to Serotonin, Tyrosine> Dopamine)
3. MTHFR
4. Folate Cycle with 5-MethylTHF+ > Methyl B12
5. Mehtylation Cycle (Mehionine) , SAMe, SAH,
6. Homocysteine> B6 input
7. Cysteine>
8. Glutathione
MTHFR
- Methylene Tetrahydrofolate Reductase
- Key Variants: C677T and A1298C
a. C677T heterozygous=40% loss of function
b. C677T homozygous=75% loss of function
c. A1298C heterozygous=20% loss of function
d. A1298C homozygous=40% loss of function
e. Compound heterozygous=40%loss of function - Cofactor(s): Riboflavin, NADH, and ATP
- Approximately 45% of the population has 1 copy of MTHFR C677T (Esp. Mexican, Italian, and Chinese).
MTHFR pathway
Draw and study