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Home , Beta oxidation, Ketosis, Protein catabolism

General Education Program Biology &

Presented by: Dr. Shaimaa Nasr Amin Lecturer of Medical Physiology • Energy is the foundation of all life. In humans energy originates within the human cell. It is there that numerous bio-chemical reactions take place to generate cellular energy in a process called • Human metabolism/cellular energy is the limiting factor in determining the quality of health an individual will experience. • Optimal metabolism results in the 100 trillion human cells to function at peak performance.

• There are two primary types of cells found in nature: 1. Eukaryotic cells – found in multi-cellular organisms such as fungi, plants, and animals (humans). 2. Prokaryotic cells - are primitive independent cells such as bacteria.

• The major difference between prokaryotes and eukaryotes is that eukaryotic cells contain membrane bound organelles in which specific metabolic activities take place. The defining organelles that set eukaryotic cells apart from prokaryotic cells are the nucleus and mitochondria. • The nucleus is the control center of the cell housing its nuclear deoxyribonucleic acid (nDNA), which contains the information needed to keep a cell operating and working properly. MITOCHONDRIA • The source of cellular energy for all eukaryotic biochemical reactions, comes from one of the cell’s organelles called the mitochondria. • Mitochondria are known as the cell’s “power house” where cellular energy is produced in the form of a molecule called – adenosine triphosphate (ATP). • Depending on the tissue, mitochondria can number anywhere from a couple of dozen (neuron) to several thousand (heart) per cell. • Another interesting fact – mitochondria have their own set of DNA –mitochondria DNA (mtDNA), which is inherited from the mother.

• Mitochondria are made from a combination of nDNA & mtDNA

ATP PRODUCTION: CELLULAR RESPIRATION • , (fats), and are the major constituents or of foods and serve as fuel for the human body. • More specifically, it is the end products of – which breaks down these macro nutrients into smaller nutrients – that are the true fuel sources for the body’s 100 trillion cells. • The major absorbed end products of food digestion are (from carbohydrates); short, medium and long-chain fatty acids (from lipids); and amino acids (from ). • All three classes of these nutrients can serve as fuel sources for the mitochondria to produce cellular energy in the form of ATP Adenosine Triphosphate (ATP)

• ATP is a high energy and is considered the cell’s “energy currency” which provides the needed energy for the cell’s many metabolic bio-chemical functions. Adenosine Triphosphate (ATP)

• ATP is a molecule which is made up of three phosphate groups and an adenosine group (ribose and adenine). Adenosine Triphosphate (ATP)

• When the “high-energy” bond between the second and third phosphate are broken a substantial amount of energy is liberated

Cellular Respiration

• The major metabolic bio-chemical pathway which is responsible for the production of ATP/cellular energy is called cellular respiration. • The sole purpose of cellular respiration is to break down glucose, fatty acids and small amounts of amino acids into ATP.

Cellular Respiration

• Cellular respiration takes place via a long step by-step process of enzymatic reactions. These enzymatic reactions can be divided into two main categories: • 1. . • 2. Aerobic Respiration Cellular Respiration

Anaerobic Respiration . Aerobic Respiration

• are the enzymatic reactions • are the enzymatic reactions that DO NOT require that DO require . oxygen. This includes the metabolic • This includes the metabolic pathways of pyruvate pathway of and oxidation, Krebs cycle and which occurs in oxidative phosphorylation the cytoplasm of the human ( & cell chemiosmosis) which all occur in the mitochondria.

ANAEROBIC RESPIRATION Anaerobic Respiration

• Glycolysis • The first stage of cellular respiration is known as glycolysis. • This stage is unique to glucose metabolism which takes place in the cytoplasm of the cell and does not require oxygen. • Through a series of biochemical enzymatic reactions the process of glycolysis breaks down glucose to pyruvate/. Anaerobic Respiration

• Glycolysis • Glycolysis also generates 2 molecules of ATP and 2 molecules of NADH. NADH is the reduced form (gained hydrogen atoms) of nicotinamide adenine dinucleotide (NAD).

Anaerobic Respiration

• Glycolysis • NAD is a co- which is derived from the – niacin (B3). Once reduced NADH acts as an electron carrier and will be transferred to the mitochondria and utilized in the electron transport chain to assist in producing additional molecules of ATP.

Anaerobic Respiration

• Fermentation • In the continual absence of oxygen (after glycolysis has been completed) the process continues to follow the anaerobic pathway and a process called fermentation. Anaerobic Respiration

• Fermentation • There are several types of fermentation, but the two most common types are /lactate fermentation and alcohol fermentation.

Anaerobic Respiration

• Fermentation • In fermentation the pyruvate/pyruvic acid molecules, which are toxic to the cell and cannot enter the mitochondria due to the lack of oxygen, are converted by into waste products.

• Also fermentation does not produce any additional energy/ATP. . Anaerobic Respiration

• Fermentation • takes place in some fungi and some bacteria like Lactobacillus acidophilus (yogurt). Anaerobic Respiration

• Fermentation • In humans, lactic acid fermentation takes place in the muscles during times of strenuous exercise or great exertion. Under these conditions the oxygen supplied by the lungs and blood system cannot get to the cells fast enough to keep up with the muscles’ demands.

Anaerobic Respiration

• Fermentation • At this point the muscle cells will switch over to lactic acid fermentation, by converting pyruvate into lactic acid via the enzyme lactic acid dehydrogenase (LDH). The build-up of lactic acid can cause cramping and a burning sensation in the over worked muscles as well as sore muscles the following day until the lactic acid is washed out of the system.

Anaerobic Respiration

• The glycolysis-fermentation pathway is important to muscle cells, by producing “some” ATP, during times when oxygen is in short supply. However, this process cannot be applied to the nerve cells/neurons in the nervous system. Anaerobic Respiration

• This is because of one major difference between nerve cells and muscle cells which is nerve cells cannot switch to lactic acid fermentation if oxygen is low. Anaerobic Respiration

• The nervous system is totally dependent, from minute-to-minute and second-to-second, on the oxygen delivered by the blood. Therefore, the lack of proper oxygen levels in the brain will result in impaired brain functioning

AEROBIC RESPIRATION Aerobic Respiration

• Pyruvate Oxidation/Transition Reaction: • After the completion of glycolysis and the production of pyruvate - if oxygen is present, pyruvate enters the mitochondria and forms acetyl-coA during the second stage called - pyruvate oxidation or transition reaction. In this stage an acetyl group is produced by cleaving off a atom from pyruvate.

Aerobic Respiration

• Pyruvate Oxidation/Transition Reaction: • The acetyl group is then bonded with (CoA) thereby forming acetyl- CoA. CoA is synthesized in the body from pantethine and cysteine. Aerobic Respiration

• Pyruvate Oxidation/Transition Reaction: • Though glycolysis is the primary source of acetyl-coA formation, acetyl-coA is also associated with the metabolism of fatty acids and amino acids. • Since acetyl-coA is common to all four pathways, it is sometimes called the “crossroads compound”. Also produced in this pathway are 2 molecules of NADH.

Aerobic Respiration

• Krebs/ Cycle/TCA Cycle • Once formed, acetyl-coA will enter into the Krebs//TCA cycle which is a “circular” series of enzymatic reactions which take place in the matrix/inner compartment of the mitochondria. Aerobic Respiration

• Krebs/Citric Acid Cycle/TCA Cycle • The result of the Krebs cycle is an additional 2 molecules of ATP , 6 molecules of NADH and 2 molecules of another electron carrier called FADH2.

Aerobic Respiration

• Krebs/Citric Acid Cycle/TCA Cycle • FADH2 is the reduced form (gained hydrogen atoms) of flavin adenine dinucleotide (FAD). FAD is a co-enzyme which is derived from the vitamin – riboflavin (B2) and once reduced it will also be used in the electron transport chain to assist in producing additional ATP. Aerobic Respiration

• Oxidative Phosphorylation: The Electron Transport Chain & Chemiosmosis • The electron transport chain is a series of five protein complexes (I, II, III, IV, V) within the cristae/inner mitochondrial membrane

Aerobic Respiration

• Oxidative Phosphorylation: The Electron Transport Chain & Chemiosmosis • And by means of a very complicated series of events the electron carriers -NADH and FADH2 produced during the earlier stages of glycolysis, pyruvate oxidation, Krebs cycle are now used to create a high gradient of hydrogen atoms in the outer mitochondrial compartment. Aerobic Respiration

• Oxidative Phosphorylation: The Electron Transport Chain & Chemiosmosis • This high gradient forces the hydrogen atoms to cross back through the cristae into the matrix. This process of transferring hydrogen atoms across the cristae is called chemiosmosis and occurs via a special membrane protein called ATP Synthase (complex V).

Aerobic Respiration

• Oxidative Phosphorylation: The Electron Transport Chain & Chemiosmosis • ATP synthase is the machinery or protein molecule that is responsible for actually producing ATP from adenosine diphosphate (ADP) and phosphate. Aerobic Respiration

• Oxidative Phosphorylation: The Electron Transport Chain & Chemiosmosis • This entire process, that takes place through the electron transport chain, and chemiosmosis generates an additional 34 molecules of ATP and is referred to as oxidative phosphorylation

ATP Tally: Glucose

• ATP the “energy currency” of the cell which was produced by means of a process called cellular respiration. Through this process it was noted that ATP was formed at various stages along with the high energy carriers – NADH and FADH2 • NADH and FADH2, are major contributors to the production of ATP via the creation of a hydrogen gradient in the electron transport chain. During this process each NADH (indirectly) yields 3 ATP while each FADH 2 (indirectly) yields 2 ATP. • the total amount of ATP produced per one molecule of glucose is:

ATP Production:

• Normally, 60% to 90% of the energy required for contraction of the heart is derived from the oxidation of fatty acids. • Also, if for some reason adequate amounts of glucose are not available such as - during times of stress, long periods between meals, and - the body cells can catabolize (break down) stored fats/lipids and even proteins for energy. /

• Lipids provide highly efficient energy storage, storing much more energy for their weight than carbohydrates like glucose. Lipids are primarily stored in (body fat) as which are composed of a backbone with three fatty acids attached.

Lipid/Fatty Acid Catabolism

• Triglycerides form fatty droplets that exclude and take up minimal space. • Fatty acids are also more highly reduced than carbohydrates, so they provide more energy during oxidation. Lipid/Fatty Acid Catabolism

• The efficiency of energy storage of lipids is probably an important reason why animals (humans) store most of their energy as fats and only a small amount of energy as carbohydrates. Lipid/Fatty Acid Catabolism

• When needed as an energy source the fat reserves are mobilized via a process called . • Lipolysis largely occurs in adipose tissue where glycerol is cleaved off of the fatty acids. Once completed the fatty acids and glycerol are then released from the adipose tissue into the blood and transported to the energy requiring tissue.

Lipid/Fatty Acid Catabolism

• In the cell glycerol – a sugar alcohol - is further converted into one of the intermediate products of glycolysis – glyceraldehyde phosphate – and then to pyruvate. Lipid/Fatty Acid Catabolism

• Glycerol makes up only 5% of the . The remaining 95% of lipid metabolism takes place when the fatty acids enter the mitochondria’s Krebs cycle. Palmitoyltransferase System (CPT) • Before fatty acids can enter the mitochondria they need to be “activated”. • The activation of fatty acids takes place in the cell’s where the enzyme acyl-CoA synthetase (ACS) - located on the “outer surface” of the outer mitochondria membrane - links the sulfhydryl group of Coenzyme A (CoA) to a fatty acid.

Carnitine Palmitoyltransferase System (CPT) • ATP drives the formation of this linkage to form a new compound called Acyl-CoA . • Once activated the short chain fatty acid acyl- CoA’s (<6 carbon atoms long) and medium chain fatty acid acyl-CoA’s (6-12 carbon atoms long) can freely diffuse into the mitochondria to be oxidized via a process called beta- oxidation. Carnitine Palmitoyltransferase System (CPT) • However, the long chain fatty acid acyl-CoA’s (>12 carbon atoms long) are unable to diffuse into the mitochondria and therefore must be transported in.

Carnitine Palmitoyltransferase System (CPT) • The transport of long chain fatty acids into mitochondria is accomplished by the carnitine palmitoyltransferase system (CPT system - CPTI & CPTII), sometimes referred to as the carnitine shuttle.

Carnitine Palmitoyltransferase System (CPT) • The CPTI enzyme, which is bound to the “inner surface” of the outer mitochondrial membrane,exchanges coenzyme A for carnitine on the long chain fatty acid acyl CoA molecule. • The bonding of carnitine forms a fatty acid- carnitine conjugate called acyl-carnitine. Carnitine Palmitoyltransferase System (CPT) • Acyl-carnitine is then shuttled across the inner mitochondrial membrane by a transporter protein/enzyme called the carnitine acylcarnitine (CACT).

Carnitine Palmitoyltransferase System (CPT) • Once acyl-carnitine has been transported into the matrix of the mitochondria CPTII exchanges carnitine for CoA, thereby, once again producing a long chain fatty acid acyl- CoA. Carnitine Palmitoyltransferase System (CPT) • Now in the mitochondria matrix, the long chain fatty acid acyl- CoA can be oxidized via a beta-oxidation. The removed carnitine is transported back through the CACT to be re- used.. Beta Oxidation

• Beta-oxidation is the process whereby all activated fatty acid (short, medium & long chain) acyl-CoA’s are oxidized, via a repeating four-step enzymatic cycle.

Beta Oxidation

• In each four-step cycle, a fatty acid is progressively shortened by having two of its carbon atoms cleaved off. • The remaining fatty acid chain re-enters the beta oxidation pathway resulting in another pair of carbon atoms cleaved off. Beta Oxidation

• This process is repeated until all the carbon atoms in the original fatty acid acyl-CoA are gone.

• The cleaved pairs of carbon atoms are used to produce acetyl groups which are then linked with coenzyme A molecules to produce molecules of acetyl-CoA.

Beta Oxidation

• acetyl-CoA is the entry point into the Krebs cycle where ATP, NADH and FADH2 are produced. • Also, during each four-step enzymatic cycle, the electron carriers NAD+ and FAD are reduced to produce (1) NADH and (1) FADH2 which are transported to the electron transport chain to assist in producing ATP.

ATP Tally: Fatty Acids

• The number of ATP produced from the breakdown of fatty acids depends on which fatty acid is utilized. • However, the following example of palmitate/, a common saturated fat found in plants and animals, will give a good example of why fatty acids are a highly concentrated source of energy. ATP Tally: Fatty Acids

• Palmitate is a 16 carbon atom and will therefore cycle through the beta oxidation pathway 7 times. • Thereby forming 7 NADH’s, 7 FADH2’s and 7 acetyl-CoA’s. • Plus the last two remaining carbon atoms will also be converted to acetyl CoA. Making the total number of acetyl-CoA produced to be 8.

ATP Production: Ketogenisis

• Ketogenesis & • Ketosis is simply the accumulation of ketones/ bodies in the body. This is a controversial subject with the debate centered on whether or not ketosis is potentially dangerous or even beneficial for some people.

ATP Production: Ketogenisis

• Ketogenesis & Ketosis • On one side of the issue it is claimed that ketones are formed due to the result of a restricted or low intake of carbohydrates. • This occurs during times of starvation, fasting, severe or when glucose is not fully utilized as in diabetes. Due to such a restricted intake, the body converts to the oxidation of more fats for energy. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • This shift occurs mainly because the entry of acetyl-coA into the Krebs cycle depends on the availabilityof (1st step in Krebs cycle), which becomes deficient in a low carbohydrate diet. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • This scenario of low oxaloacetic acid levels will in turn cause fatty acid oxidation to be incomplete thereby causing an excess of acetyl-coA to accumulate in the cells. The excess acetyl-coA is transported to the • where it is converted to ketones via a process called ketogenesis ATP Production: Ketogenisis

• Ketogenesis & Ketosis • Since most ketones are acidic, in certain people ketosis can lead to metabolic or which is an increase in blood and tissue acidity which can be dangerous. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • The body eliminates most ketones (i.e. ) by excreting them through the urine as well as the breath. Ketones excreted through the breath give a person’s breath a sweet, fruity smell that has been likened to the smell of nail varnish. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • The physiological significance of these takes the form of ATP production. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • There is limited transport of fatty acids across the blood-brain barrier, which explains why fatty acids are not a significant fuel source for the brain. Ketone bodies, however, can cross the blood brain barrier and can therefore be an alternative source of energy for the brain. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • Unlike glucose, the uptake of ketone bodies occurs via the family of monocarboxylate transporters (MCTs), which are not mediated.” ATP Production: Ketogenisis

• Ketogenesis & Ketosis • MCT proteins enable ketones to pass readily through the blood-brain barrier. Many types of peripheral cells, including brain cells, not only use glucose, but also use ketones to produce acetyl-CoA.” ATP Production: Ketogenisis

• Ketogenesis & Ketosis • ATP is produced by ketones when the ketone bodies – beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) enter the mitochondria and are acted upon by several enzymes. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • Ketolysis – the splitting up of ketones – takes place first when 3-oxoacid-CoA transferace (OCT) adds coenzymeA to AcAc, which is then split into two molecules of acetyl-CoA by acetoacetyl-CoA (ACT). The acetyl- CoA molecules then enter into the Krebs/TCA cycle ATP Production: Ketogenisis

• Ketogenesis & Ketosis • In the liver, much of the acetyl CoA generated from beta-oxidation of fatty acids is used for synthesis of the ketone bodies acetoacetate and beta-hydroxybutyrate, which enter the blood. ATP Production: Ketogenisis

• Ketogenesis & Ketosis • In skeletal muscles and other tissues, these ketone bodies are converted back to acetyl- CoA, which is oxidized in the TCA cycle to produce ATP. • ketones are basically water soluble fats which dissolve in blood. And are a source of energy for many tissues including the muscles, brain and heart. • Though ketones can’t totally replace all the sugar required by the brain, they can replace a good chunk of it.

ATP Production: Protein/ Catabolism • The first step in is to digest protein molecules into individual amino acids. Once this is done the removal of the amino group (NH2) is required and takes place in the liver via a process called deamination. The removed amino group is converted to ammonia (NH3). ATP Production: Protein/Amino Acid Catabolism • Ammonia is highly toxic and is further converted in the liver to urea and then excreted from the body via the kidneys. ATP Production: Protein/Amino Acid Catabolism • Once the amino group is removed the remaining carbon skeleton – a - can enter the cellular respiration cycle either as pyruvic acid (50%), acetyl CoA (25%) or enter directly into the Krebs/citric acid cycle (25%) to generate ATP (different amino acids go through different pathways). ATP Production: Protein/Amino Acid Catabolism • Catabolism of amino acids is not a practical source of quick energy and is typically only used in starvation situations. • ATP Production: Protein/Amino Acid Catabolism • Proteins are harder to break apart than carbohydrates or lipids, their catabolism generates toxic waste products (ammonia), and they are the structural and functional parts of every cell, and thus tend to only be used when no other energy source is available.

ATP Production: ATP Turnover

• Regardless of the source of ATP – glycolysis, beta-oxidation, Krebs cycle, oxidative phosphorylation –ATP needs to be “turned over” so that it is re-used over and over. This is to supply the body with the huge amounts of ATP it demands, of which cannot be produced in such volumes from scratch by normal metabolic pathways. ATP Production: ATP Turnover

• The turnover process takes place naturally by means of a protein called adenine nucleotide translocator (ANT) or ATP-ADP translocase. Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • The production of ATP, via ATP synthase, occurs on the inside of the mitochondrial inner membrane – in the matrix. But most of the cellular ATP usage is required outside the mitochondria - in the cytosol. • Therefore ATP needs to be transported from the mitochondria’s matrix to the cell’s cytosol. Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • This is accomplished through a special protein called adenine nucleotide translocator (ANT) or sometimes referred to as the ATP- ADP translocase which is located on the inner membrane of the mitochondria.

Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • ANT is the most abundant protein of the inner mitochondrial membrane and is the most active enzyme in animal (human) cells. Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • Once transported into the cytosol, ATP undergoes hydrolysis via the enzyme • ATPase. ATPase breaks the phosphate bonds and thereby releasing energy to be used for the cells many biochemical functions. Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • This process also results in the formation of a new molecule -adenosine di-phosphate (ADP) and a phosphate molecule. ANT will now be used to transport the ADP molecule back into the matrix for reprocessing.

Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • ANT simultaneously transports both ATP and ADP. For each ATP molecule transported out of the matrix, one molecule of ADP is transported into the matrix.

Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase • Once in the matrix ADP and phosphate are re- synthesized via ATP synthase to produce a new molecule of ATP starting the cycle all over. ATP Production: The ATP–CP System

• The ATP-CP System. Unlike the normal metabolic pathways this pathway or system is exclusive to muscle (includes cardiac), brain and eye cells only. The ATP-CP system is a non-lactic acid producing, anaerobic (without oxygen) system whose primary use is for quick short-acting bursts of energy. The ATP– Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• When the body is at rest energy needs are fulfilled by aerobic catabolism because the low demand for oxygen can easily be met by oxygen exchange in the lungs and by the oxygen carried to the muscle by the cardiovascular system. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• If physical activity is initiated, the energy requirements of contracting muscle are met by existing ATP. • However, stores of ATP in muscle are limited, providing enough energy for only a few seconds. If the physical activity continues ATP levels diminish as it is converted to ADP. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• Luckily, the body has a small reservoir of creatine phosphate(CP)/phosphocreatine (PCr) which can be used to quickly regenerate ADP into ATP. Creatine phosphate is nothing more than a molecule of creatine with a phosphate molecule bonded to it. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• This process is catalyzed by the enzyme creatine kinase (CK), and the reaction is reversible. The enzyme can either add a phosphate to creatine to make creatine phosphate, or remove one to make creatine, depending on the needs of the cell

The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• This process is catalyzed by the enzyme creatine kinase (CK), and the reaction is reversible. The enzyme can either add a phosphate to creatine to make creatine phosphate, or remove one to make creatine, depending on the needs of the cell The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• Creatine phosphate is found in muscle, brain and eye cells in the amount of 4 to 6 times greater than that of ATP. Thus most energy is stored at these sites in creatine phosphate pools.

The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• Because only one enzymatic reaction is involved in this energy transfer, ATP can be formed rapidly (within a fraction of a second) by using creatine phosphate. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• At rest, muscle fibers produce more ATP than is required by the body. This excess ATP is used to synthesize creatine phosphate. • The enzyme creatine kinase catalyzes muscles fibers to break down excess ATP and transfer a phosphate group to creatine, forming creatine phosphate and ADP.

The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• During contraction, muscle fibers transfer the phosphate group from creatine phosphate to ADP, forming ATP. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• All though the ATP-CP system creates ATP almost instantly, it does have its limits. • In that in can only produce about 15 seconds worth of physical activity. Although this may seem like a very limited amount of time, creatine phosphate provides the muscles with ATP before aerobic respiration can take over. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• The ATP-CP system is active at the beginning of all forms of activities but is especially important in high intensity exercises that require short bursts of energy. The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• All though the ATP-CP system creates ATP almost instantly, it does have its limits. In that in can only produce about 15 seconds worth of physical activity. Although this may seem like a very limited amount of time, creatine phosphate provides the muscles with ATP before aerobic respiration can take over The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System

• The ATP-CP system is active at the beginning of all forms of activities but is especially important in high intensity exercises that require short bursts of energy.

The Methylation Connection

• Methylation is one of the most common metabolic functions of the body, occurring in the order of a billion times per second. It is the process by which a methyl group (CH3) is transferred from one molecule (a methyl donor) to another (which becomes 'methylated'). The Methylation Connection

• over 100 different biochemical reactions in the body, which are catalyzed by methlytransferase enzymes, influencing such things as: - Energy (co-q10, carnitine, creatine) - Cell membrane growth & repair (myelin, phospholipids) - (, nor- adrenaline, dopamine, serotonin, histamine) The Methylation Connection

• over 100 different biochemical reactions in the body, which are catalyzed by methlytransferase enzymes, influencing such things as: - Hormones (thyroid, adrenal, ) - Immunity (T-cells, autoimmunity, histamine, TH1/TH2 balance, viral DNA, NK cell function) - DNA & RNA - Detoxification (sulfur metabolism, glutathione, ) The Methylation Connection

• The main methyl donor in the body is called S-adenosylmethionine (SAMe). Levels of SAMe are maintained by a basic cellular biochemical cycle, called the methylation cycle. Whereby SAMe is synthesized from the amino acid methionine.

Methylation & Coenzyme Q10 Synthesis • Coenzyme Q10 (CoQ10) is a vital component of the electron transport chain where it is responsible for the transfer of electrons between complex I, II & III. • Without out CoQ10 there would be no ATP production. Methylation & Coenzyme Q10 Synthesis • CoQ10 is a non-essential which is naturally produced in the human body and is synthesized from the amino acid tyrosine and precursor molecules. Two of the final steps in the biosynthesis of CoQ10 involve methylation by SAMe Methylation & Carnitine Synthesis

• Carnitine is responsible for the shuttling of long chain fatty acids across the mitochondrial membrane so they may be used in the beta-oxidation system. Methylation & Carnitine Synthesis

• Carnitine is a non-essential nutrient which is naturally produced in the human body from - the synthesis which begins with the methylation of the amino acid by SAMe. Methylation & Carnitine Synthesis

• After several more steps requiring consecutive methylations and the interaction of several enzymes, and minerals – carnitine is produced in the body. Methylation & Creatine Synthesis

• The ATP–creatine phosphate system is the body’s energy reserve tank. Supplying energy for quick short • acting burst of energy. Methylation & Creatine Synthesis

• Creatine is a non-essential nutrient which is naturally produced in the human body from the amino acids glycine, aginine and methionine. The synthesis of creatine occurs primarily in the kidneys and liver. Methylation & Creatine Synthesis

• Once synthesized, creatine is transported in the blood for use by muscle tissue, brain and the eyes. • Approximately 95% of the human body's total creatine is located in muscle tissue. Methylation & Creatine Synthesis

• The synthesis of creatine, via methylation, is the single greatest drain of the body’s methyl reserves, consuming over 70% of the body’s entire supply. • Furthermore, given that the body’s methyl reserves are limited in size, creatine synthesis alone could potentially create a state of methyl-deficiency. Methylation Cycle & Adenosine

• Adenosine is a molecule, made up of ribose and adenine, which form the back bone to the all-important molecule this report has centered on – adenosine tri- phosphate (ATP), adenosine di-phoshpate, (ADP), and adenosine mono-phosphate (AMP) Methylation Cycle & Adenosine

• Adenosine can be synthesized in the body through a couple of pathways, but a key pathway is through the methylation cycle. In the methylation cycle SAMe is enzymatically converted into an intermediate molecule called S-adenosylhomocysteine (SAH). And via a series of enzymatic activities SAH can be converted to adenosine or any one of its by products →AMP →ADP→ATP.