Taurine:

A Mysterious Molecule with Intriguing Possibili8es

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Outline
1. Introduction 2. Some Biochemistry 3. Some Observed Benefits of Taurine
The The The The The Skin Heart Pancreas Brain Blood

4. 5. 6. 7.

Mitochondrial Diseases Encephalitis Cancer Summary

1. Introduction

 Have you thought about taurine?*

* Ann Lauritzen, Wise TradiFons Workshop, WAPF 2011, Dallas, TX

What is Taurine?
Taurine is the most common free amino acid in the body Taurine is never incorporated into any protein, and it hardly ever parFcipates in any reacFon Yet taurine is found in high concen- traFon in the heart, brain, and liver What is it doing there???

Some Interes8ng Facts about Taurine*

Important in many marine species for osmosis (as an osmolyte)
Shallow water clams and snails have signicantly more than deeper water species

Cats become blind if raised without taurine Brain taurine levels decline with age in mammals; replaced with glutamate

Argument used to jusFfy presence in energy drinks

* P.H. Yancey, J Experimental Biology 208, 2819-2830, 2005.

Taurine has Many Known Roles*

Maintains osmoFc balance in cells Bile acid formaFon (digest fats) Roles in mitochondria Clinical observaFons

Helps them maintain their membrane potenFal Suppresses superoxide synthesis (oxidaFon damage) Maintains healthy skin Protects against diabetes and heart disease Protects against heart arrhythmias Low taurine in blood associated with many cancers
* Wesseling et al., Hypertension. 2009, 53, 909-911

 Taurine is found only in animal-based foods

Food Sources of Taurine

Eggs, meat, sh, seafood, dairy

Fish Oil + Taurine*

Experiment on diabeFc/obese mice, three groups
Fish oil Fish oil + taurine Soybean oil

Serum glucose levels signicantly lower in mice fed sh oil (with or without taurine) Fish oil + taurine group had enhanced GLUT4 distribuFon in plasma membrane of muscle Fssue.
GLUT4 is the key catalyst for glucose uptake in muscles

*Mikami et al., J. Food Sci. 2012 Jun, 77(6), H114-20.

A Provoca8ve Hypothesis
Taurine is very stable (many claim it is inert) Taurine is stored in heart and brain as buer for sulfate supply during extreme adverse condiFons EncephaliFs leads to sulfate renewal!
Hypochlorite (bleach) [released by immune cells to ght infecFon] Fever [enhances energy of reacFon] Seizures [induce electric current and provide free electrons]

-2 The Importance of Sulfate: SO4

I have traced most modern diseases to a deciency in the supply of sulfate (I will talk much more about this tomorrow) Two criFcal points:
SulfaFon of cholesterol is essenFal for cholesterol transport sulfate deciency implies cholesterol deciency SulfaFon is essenFal for managing sugar: insucient sulfate supply leads to diabetes

2. Some Biochemistry

Taurine!

Is Taurine an Amino Acid?

Sulfonyl

Carboxyl is replaced by Sulfonyl

Taurine Synthesis Pathway*

EssenFal amino acid * Wesseling If et y al., ou have to Hypertension. 2009, taurine synthesize 53, 909-911 Source of sulfate

from precursors, these other roles are sacriced!

EssenFal to protein folding

Potent anFoxidant

Big Hints from Early Literature*

ArFcle published in 1960 Fed cholesterol to monkeys
Induced atherosclerosis

If sulfur-containing nutrients are added, atherosclerosis is prevented Taurine worked as well as other molecules like cysteine, methionine, and glutathione
* G.V. Mann et al., Am. J. Clin. Nutr. 8, 491-497, 1960.

Breaking down Taurine to get Sulfate

A Hint: hypochlorite is released Citric Acid Cycle by neutrophils to ght infecFon

Such a reacFon might be possible in the human, but its not easy

Another Useful Reac8on

C2H7NO3S + H2O NH4+ CH3COO- + H2S + O2 taurine + water ammonia + acetate + hydrogen sulde + oxygen cysteine
N-acetyl cysteine VasorelaxaFon Oxidize to thiosulfate & cholesterol sulfate Generate ATP
NutriFonal supplement for Tylenol overdose and to treat sulfate deciency in auFsm

3. Some Observed Benefits of Taurine

Taurocholic Acid: in Bile Acids

Makes bile acids more water soluble Aids in digesFng fats

cholesterol

taurine

The Skin

SLS: a Skin Irritant*

Sodium lauryl sulfate (SLS) is added to shampoos mainly to make them foamy Surfactant ( = surface acFve agent) Used in many commercial formulaFons because it is inexpensive, oers great foaming, and can be thickened easily with salt SLS is a skin irritant -- induces dry, scaly skin due to its surfactant eects
* Lee and Maibach, Contact DermaFFs, 1995, 13, 1-7

Taurine, SLS, and the Skin*

Taurine accumulates in outermost keraFnocyte layer of the skin following UV exposure
SFmulates synthesis of ceramides, cholesterol, and fa2y acids

SLS induces an increase in water loss through the skin, inammaFon, and proliferaFon IncubaFon w/ SLS + taurine

Decrease in IL-1 and prostaglandin E2 (inammatory agents) StabilizaFon of membrane integrity Improvement in keraFnocyte viability

* B. Anderheggen et al., J Cosmet Sci. 2006 Jan-Feb;57(1), 1-10

The Heart

Sudden Cardiac Death*

Sudden cardiac death is the leading cause of death in industrially developed countries Accounts for 300,000 - 500,000 deaths per year in U.S. Due to ventricular brillaFon: life-threatening heart arrhythmia Manifested by low heart rate variability Triggered by adrenalin in response to stress Intracellular potassium and calcium dysregulaFon insucient membrane cholesterol?

* G.E. Billman, Am J Physiol Heart Circ Physiol 297:H1171-H1193, 2009

Cardioprotec8ve Eects of Taurine*

Taurine is normally found in highest concentraFon in the heart AnFarrhythmic eects observed experimentally in cats, dogs and guinea pigs. AddiFon of taurine
Prevents loss of potassium by myocardium Reverses adverse eects of adrenalin and digoxin Eliminates the pathological ECG changes caused by strophanthin in isolated guinea pig hearts.

My hypothesis: Is taurine a source of sulfate for cholesterol sulfate synthesis?

* Georgy Eby, Taurine Role in Cardiology and Cardiac Arrhythmias h2p://george-eby-research.com/html/taurine.html

High Dietary Taurine Reduces Apoptosis (Cell Death) and Atherosclerosis*

High dietary sh associated with decreased cardiovascular death rate
Taurine is highly concentrated in sh

High dietary taurine reduces risk of coronary heart disease and insulin resistance Taurine deciency can also lead to obesity, a risk factor for heart disease

* A. Zulli et al., Hypertension, 53, 1017-1022, 2009

High Dietary Taurine Reduces Apoptosis and Atherosclerosis: Experiment*

Rabbits fed high cholesterol diet Examined eect of taurine supplements on lex main coronary artery Results
Reduced serum homocysteine levels Endoplasmic ReFculum stress reduced in endothelial cells which protected them from apoptosis Reduced atherosclerosis in artery wall Reduced serum HDL

* A. Zulli et al., Hypertension, 53, 1017-1022, 2009

High Dietary Taurine Reduces Apoptosis and Atherosclerosis*: My Interpreta8on

Taurine reacted with hypochlorite which allowed it to be metabolized to sulfate
Protected LDL from hypochlorite toxicity Reduced uptake of LDL into plaque

Platelets uFlized newly available sulfate to produce cholesterol sulfate from cholesterol obtained from HDL
Depleted HDL

Homocysteine could be diverted to cysteine and glutathione instead of being held in reserve as an alternaFve source of sulfate.
Serum homocysteine levels dropped
* A. Zulli et al., Hypertension, 53, 1017-1022, 2009

Recapitula8on
Sudden cardiac death is leading cause of death in Western naFons Taurine is highly concentrated in the heart Low dietary taurine associated with increase in insulin resistance, obesity, and heart disease Taurine protects rabbits from cholesterol-diet- induced cardiovascular disease I hypothesize that these eects are due to taurine's ability to promote cholesterol sulfate synthesis
Protects from sudden cardiac death

The Pancreas

Taurine and Pancrea8c Islet Cells*

Mother rats fed low-protein diet during gestaFon This s hows h ow maternal diet and lactaFon can have long- Ospring had vulnerable term e ects o n islets in their pancreas ospring! (leading to diabetes)
Excess producFon of toxic nitric oxide Increased apoptosis (cell death)

Supplement with taurine in protein-decient mothers alleviates these eects

* K Goosse et al., Journal of Endocrinology (2009) 200, 177187

Taurine, Fructose, and Diabetes*

Fructose induces diabetes
Rats fed cornstarch compared with rats fed fructose (60% of dietary calories) Fructose induced insulin resistance (well-known response)

Supplement with 2% taurine soluFon ad libitum protected rats from insulin resistance
* Nandhini et al., Singapore Med J, 46(2), 82-87, 2005

Taurine, Fructose, and Diabetes*

Taurine Completely Eliminated the Sugar Spike Caused by Fructose

CON= cornstarch FRU = fructose TAU = taurine

* Nandhini et al., Singapore Med J, 46(2), 82-87, 2005

The Brain

Taurine in Development*
Highest concentraFon occurs in developing brain Taurine concentraFons fall during development
Converted to sulfate?

Neonates have 3x levels of adults True for humans, monkeys, mice, rabbits, rats, and insects
* R.J. Huxtable, Physiological Reviews 72(1), 101-163, Jan 1992

Taurine is Neuroprotec8ve*
Taurine prevents excitotoxicity induced by glutamate in neurons Mitochondrial electron gradient mitochondrion is calcium regulated AcFvaFon by glutamate
Extracellular calcium inux MobilizaFon from internal stores (mitochondria) Associated with decrease in mitochondrial energy metabolism

Pretreatment with taurine normalized calcium homeostasis and prevented mitochondrial impairment

* A. El Idrissi and E. Trenkner, J. Neuroscience, 19(21), 9459-9468, 1999.

The Blood

Taurine Protects Platelets from Blood Clots*

Taurine is especially concentrated in nervous system and platelets Cats are oxen aicted with a taurine-deciency cardiomyopathy along with arterial thromboembolism - Blood clot blocks ow to heart Taurine suppresses release of thromboxane by platelets which triggers blood clot formaFon - Study conrmed this is true for humans as well

* K.C. Hayes et al., Am. J. Clin. Nutr. 1989; 49:1211-6.

Sub-op8mal taurine status may promote platelet hyperaggregability in vegetarians*

Plasma taurine levels are lower, and urinary taurine excretion is substantially lower, in vegetarians than in omnivores. Platelets are rich in taurine, which functions physiologically to dampen the calcium influx evoked by aggregating agonists thereby down-regulating platelet aggregation.

* M.F. McCarty, Medical Hypotheses, 63(3), 426-433, 2004.

Outline
1. Introduction 2. Some Biochemistry 3. Some Observed Benefits of Taurine
The The The The The Skin Heart Pancreas Brain Blood

4. 5. 6. 7.

Mitochondrial Diseases Encephalitis Cancer Summary

4. Mitochondrial Diseases

Mitochondrial Diseases*

Mitochondria convert food into ATP for energy Mitochondrial stage I impairment associated with many neurological and muscular disorders Mitochondrial Diseases
Oxen caused by mutaFons in mitochondrial genes Symptoms include poor growth, loss of muscle coordinaFon, muscle weakness, visual problems, hearing problems, learning disabiliFes, heart disease, liver disease, kidney disease, gastrointesFnal disorders, respiratory disorders, neurological problems, autonomic dysfuncFon, and demenFa.
* From Wikipedia

Human mitochondrial diseases caused by lack of taurine modica8on in mitochondrial tRNAs*

* Kirino and Suzuki, RNA Biology 2(2), 41-44, June 2005.

Defects from Gene8c Mitochondrial Disorders* MutaFons prevent taurine a2achments to

tRNAs
(1) Impair UUG gene translaFon (taurine)
NADH-Coenzyme Q reductase impaired Mitochondrial Complex I disrupted

(2) Impair AAA and AAG (taurine + S)

Defect in whole mitochondrial translaFon QuesFon: Does the addiFonal S play a highly signicant role in enabling gene translaFon??

Generic taurine deciency might lead to similar mitochondrial impairments

* Kirino and Suzuki, RNA Biology 2(2), 41-44, June 2005.

Fever, Au8sm, and Mitochondria*

Found a plausible link between mitochondria, fever, and taurine Fever impacts auFsm
Some regress axer fever, some improve Subset with mitochondrial dysfuncFon regress

Aggressive treatment may worsen outcome

Acetaminophen (Tylenol) depletes sulfate Fever suppression prevents sulfate regenera4on from taurine?

* Shoner et al., J Child Neurol. 2009 Sep 22

ASD (1 in 110 children born) 14% of the children with both auFsm and mitochondrial disease suered regression Children with ASD and mitochondrial disease following vaccinaFon 60% with regression events
70% with fever or infecFon

Fever Plus Mitochondrial Disease Could Be Risk Factors for Au8s8c Regression* with All children

1/3 with vaccinaFon

* h2p://blog.auFsmspeaks.org/2010/03/11/fever-regression/

5. Encephalitis

A Provoca8ve Proposal: Encephali8s is Protec8ve!

Taurine is kept in reserve as a buer for sulfate supply EncephaliFs enables conversion of taurine to sulfate This is an important posiFve outcome of encephaliFs

What is Encephali8s?
EncephaliFs is an acute inammaFon of the brain
Usually caused by infecFon, most oxen by a virus, but someFmes by bacteria, a fungus, or a parasite.

Symptoms
Headache Fever Confusion Sleepiness FaFgue Seizures and convulsions Tremors Memory problems

Figh8ng the Infec8on: Nitric Oxide and Hypochlorite

Neutrophils follow microbes into brain A2ack microbes with anFmicrobial agents: hypochlorite Neutrophil Nitric - Nitric oxide oxide taurine chloramine - Hypochlorite Excess nitric oxide ammonia ammonia taurine complex reacFon in the astrocyte Frees up taurine to protect from hypochlorite damage (by becoming taurine chloramine)
Astrocyte

Taurine Chloramine is Energized!

Although it is believed that taurine is inert, taurine chloramine can be metabolized to sulfate!! (at least by some species) Can humans do this?? maybe!

Some More Help from Astrocytes

Astrocytes release both taurine and glutamate axer swelling in response to ammonia exposure Glutamate is an acFve neurotransmi2er capable of inducing a 2Hz resonance phenomenon
This could be a key source of seizures Seizures provide electric current

Glutamate Cycling
Glutamate is an acFve neurotransmi2er Conversion to glutamine renders it inacFve during transport
mitochondrion

glutamate Ammonia

glutamine PresynapFc neuron

Synapse Astrocyte PostsynapFc neuron

Glutamate during Encephali8s

During encephaliFs, astrocyte releases ammonia from glutamine in mitochondria and ships out glutamate
mitochondrion Glutamate can induce seizures glutamate Ammonia

glutamine PresynapFc neuron

ammonia Synapse Astrocyte PostsynapFc neuron

Why is Ammonia Needed in the Mitochondrion?

To replace taurine! Astrocyte releases both taurine and glutamate into the medium Ammonia replaces taurine as buering agent in mitochondria
Helps them maintain basic pH THIS FREES UP TAURINE TO PRODUCE SULFATE!!!

Glutamate during Encephali8s

Ammonia replaces taurine in mitochondrion and frees up taurine for something else!
mitochondrion glutamate Ammonia

glutamine

TAURINE!
ammonia

PresynapFc neuron

Synapse Astrocyte PostsynapFc neuron

Hypochlorite + Taurine Salva8on!

hypochlorite taurine chloramine

Neutrophil

Nitric oxide ammonia

taurine

Astrocyte

A Role for Microbes!*

Hypothesis: brain infecFon allows bacteria to supply sulfate to the brain Under stress condiFons, glutamate is released by astrocytes in the brain and metabolized to -ketoglutarate in the neurons (subsFtutes for glucose metabolism to generate energy) E coli and many other bacteria can uFlize the enzyme -ketoglutarate dioxygenase to metabolize taurine
Inputs oxygen, -ketoglutarate, taurine Outputs carbon dioxide succinate, sulte and aminoacetaldehyde This enzyme is induced during sulfate starvaFon Sulte is easily oxidized to sulfate

Microbes allowed to ourish in the brain to supply sulfate!

*K.P. McCusker and J.P. Klinman *Tetrahedron Le2ers 50 (2009) 611613

Recapitula8on
EncephaliFs may be a mechanism to renew sulfate supply to the brain, by breaking down taurine Complex mechanism involves glutamate, hypochlorite, nitric oxide, ammonia, etc. Fever and seizures also provide catalysis Bacteria may be permi2ed into the brain to help carry out the reacFon

6. Cancer

Taurine and Breast Cancer*

Progressive inhibiFon of apoptosis (cell death) and inducFon of angiogenesis (blood vessel growth) contribute to tumor iniFaFon, growth and metastasis in the pathogenesis of breast cancer Taurine displays anFneoplasFc eects through
DownregulaFon of angiogenesis Enhancement of tumor cell apoptosis

* I. M. El Agouza et al. Angiogenesis 14, 321330, 2011

Taurine and Breast Cancer*

85 women
50 with diagnosed breast cancer 10 with benign tumors 5 with family history 20 controls

Serum taurine sharply reduced in women with breast cancer (p<0.001)

100% detecFon, 0% false alarms
* I. M. El Agouza et al. Angiogenesis 14, 321330, 2011

Taurine and Breast Cancer*

16 14 12 10 8 6 4 2 0 control high risk group cancer paFents

VEGF accelerates growth

69-fold increase
VEGF/TNF VEGF/taurine

* I. M. El Agouza et al. Angiogenesis 14, 321330, 2011

Taurine Induces Apoptosis*

Proliferate
Tumor cell

VEGF
Tumor cell

Tumor cell

TNF-

Tumor cell

Die

Tumor cells are robust against exposure to toxic agents; they proliferate while other normal cells die * A. Jacobi et al, AnFcancer Drugs 16(9), 917-921, 2005.

Taurine Induces Apoptosis*

+ Taurine
VEGF
Tumor cell

Proliferate
Tumor cell Tumor cell

TNF-

Tumor cell

Die

Tumor cells are robust against exposure to toxic agents; they proliferate while other normal cells die * A. Jacobi et al, AnFcancer Drugs 16(9), 917-921, 2005.

Low Serum Taurine and Cancer

Many dierent cancers have been found to be associated with unusually low serum taurine levels
Breast cancer Ovarian cancer Hypothesis: cancer Bladder cancer depletes taurine by Lung cancer converFng it to sulfate Uterine cancer Liver cancer Tumor cells typically Colon cancer overproduce sulfated Gastro-intesFnal cancer polysaccharides Endometrial cancer

7. Summary

Food Sources of Taurine

Eggs, meat, sh, seafood, dairy

Summary
Taurine is a fascinaFng and poorly understood molecule! We need to worry about dietary deciencies, especially vegetarians Taurine is protecFve in cancer, heart disease, and diabetes i.e., the major diseases of modern Fmes Taurine plays an essenFal role in development Taurines many benets may stem from its role in supplying a buer for sulfate to the body

Thank you!

Hydrogen Sulde Protects Mitochondria *

* Figure 10 in L.-F. Hu et al, Mol Pharmacol 75:2734, 2009

Taurine-modied tRNAs in Mitochondria*

* From Suzuki et al., WIREs RNA 2011, 2, 376-386