Metabolism and its control PDF

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Metabolism and its ControlExplain how animal cells convert acetyl-CoA to long-chain fattyacids- Fatty acids synthesis creates fatty acids from acetyl-coA and NADPH- They’re build up in sections of 2 carbon units at a time- Each addition of a 2 carbon unit to the growing fatty acid chain requires six...

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Monday, 25 November 2019

Metabolism and its Control Explain how animal cells convert acetyl-CoA to long-chain fatty acids!

- Fatty acids synthesis creates fatty acids from acetyl-coA and NADPH ! - They’re build up in sections of 2 carbon units at a time! - Each addition of a 2 carbon unit to the growing fatty acid chain requires six recurring reactions !

- This reaction proceeds until the chain reacher 16-carbons unit ! - Firstly, acetyl-coA must be exported out of the mitochondria before use! - Fatty acid occurs in the cytosol! - Acetyl coA therefore needs to be transported from the mitochondria! - To achieve this, acetyl coA is combined with oxaloacetate to form citrate! - The citrate is broken down in the cytosol to yield acetyl-coA and oxaloacetate! - After acetyl-coA is found in the cytosol it is converted into acetyl-ACP! - ACP stands for acetyl carried protein, a physical component of mammalian fatty acid synthase protein!

- In later phase of fatty acid synthesis, the acetyl group is replaced with a longer acyl chain!

- Malonyl coA is converted to malonyl-ACP! - This is done by removing the CoA and replacing it with binding to the second ACP domain of the fatty acid synthase!

- Malonyl coA is formed by carboxylating acetyl-coA using up one ATP ! - The enzyme brings malonyl and acetyl groups close together! - These react and form a 4 carbon acyl chain! - One molecule of CO2 is released and a free thiol group is restored at an ACP part of the protein!

- This thiol group is free to accept another malonyl-coA! - The carbon 3 ketone is reduced to a hydroxyl group using NADPH as a reducing agent!

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- NADP is generated in this.! - Then a water molecule is removed in a dehydration reaction! - The C2-C3 double bond is reduced to yield a saturated acyl chain attached to the ACP. This is a reduction.!

- NADPH is used as a reducing agent generating NADP in the process.! - This cycle is repeated so that the ACP acyl chain is extended 2 carbon at a time.! - Meaning the cycle is repeated 6 more times until the chain reached 16 carbons! - The cycle consumes 1 acetyl-coA, 1 ATP and 2 NADPH each turn. ! - Overall, 8 acetyl-CoA + 14 NADPH + 7 ATP will yield palmitate+14NADPH+8coA+7ADP and 7 Pi!

- The fatty acid can then be bound to glycerol which is formed during glycolysis ! - This yield triglyceride.! Describe how glucose is converted into energy in animal cells!

- In order to turn glucose into energy into the cell, glucose must undergo three pathways.!

- These are glycolysis, the Krebs cycle and the electron transfer chain.! - Glycolysis is the first step, occurring within the cytoplasm of the cell. ! - It has a net gain of 2 ATP and ultimately yields pyruvate.! - Glycolysis has two phases :! - An investment phase where ATPs are spent! - Pay off phase where ATPs are gained! - Starting with the investment phase! - Glucose is first phosphorylated by the hexokinase. ! - This requires an ATP from where the phosphate group is removed.! - This yields Glucose-6-Phosphate! - Glucose-6-Phosphate is then isomerised into Fructose-6-Phosphate! - This is catalysed by phosphoglucose isomerase! - Fructose-6-Phosphate is phosphorylated into Fructose-1,6-biphosphate! 2

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- This is catalysed by phosphofructokinase! - This reaction once again requires an ATP! - Fructose-1,6-biphosphate is then split into G3P (glyceraldehyde 3 phosphate) and DHAP (dihydroxyacetone phosphate) !

- This is catalysed by adolase! - This marks the end of the investment phase the beginning of the pay off phase! - DHAP is then rearranged into G3P by the action of triose phosphate isomerase! - G3P gets turned into 1,3-Biphosphoglycerate by the action of glyceraldehyde-3phosphate dehydrogenase!

- This reaction yield 1 NADPH! - 1,3-Biphosphate is turned into 3-phosphoglycerate by the action of phosphoglycerate kinase.!

- This reaction yields ATP ! - 3-Phosphoglycerate then turns into phosphoenolpiruvate PEP by the action of enolase !

- H20 is also formed! - PEP then turns into pyruvate by the action of pyruvate kinase! - This forms another ATP. ! - Pyruvate is then fed into the second metabolism pathway the Krebs cycle! - Pyruvate has to enter the mitochondria matrix where the Kreb cycle happens ! - To do so pyruvate is turned into acetyl coA so it can enter the mitochondrial matrix!

- This is done by pyruvate dehydrogenase which yields a NADPH in the process.! - Once in the mitochondrial matrix acetyl-coA is turned into citrate! - This is done by citrate synthase! - Citrate turns into Isocitrate ! - This is catalysed by aconitase! - Isocitrate is turned into alpha ketoglutarate by the action of isocitrate dehydrogenase !

- This yields NADH and CO2! 3

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- Alpha ketoglutarate turns into succinyl-coA by action of alpha ketogluturate dehydrogenase!

- Once again NADH is yielded! - Succinyl-coA converts into succinate by the action of succinyl-coA synthase! - This yields GTP and coA! - Succinate turns into fumarate by the action of succinate dehydrogenase ! - This yield FADH2! - Fumarate is turned into Malate by fumarate.! - This reaction requires H2O! - Finally Malate turns into oxaloacetate by the action of malate dehydrogenase ! - This yields NADH! - Oxaloacetate can then be turned into citrate by citrate synthase and the cycle begins again!

- Overall, one pyruvate molecule yield 1 FADH2, 3 NADH and one GTP! - FADH and NADH are then shuttled into the electron transfer chain! - The electron transfer chain occurs in the inter membrane of the mitochondria! - It is used to convert the energy of high energy molecules like NADH and FADH into ATP!

- To do this a hydrogen ion gradient is gonna be created! - The four complexes will achieve this by pumping electrons across the membrane and out the matrix!

- The proton motive force derives both from the H+ ion concentration gradient AND the voltage across the membrane!

- The hydrogen ions experience a strong “pull” back into the matrix - this is called the proton motive force!

- NADH starts by donating its 2 electrons to Complex I! - The electrons travel through Complex I until they reach the out to be sent to Coenzyme Q!

- coQ floats freely within the membrane! - At the same time, 4 hydrogen ions are pumped out! 4

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- 2 electrons from FADH2 are shuttled through complex II onto CoQ! - There is no direct pumping of electrons by complex II so the energy is passed to CoQ!

- Complex III collects the energy from CoQ! - Complex III shuttles the two electrons from CoQ onto cytochrome c, which floats freely in the inter-membrane space!

- At the same time, complex III pumps 2 H+ ions out of the matrix, and a further 2 H+ ions from CoQH2!

- Complex IV receives one electron at a time from loaded Cyt c! - The electrons are shuttled through complex IV to molecular oxygen, which is the final oxidising agent of respiration!

- Water (H2O) is produced, and 1 H+ ion is pumped out of the matrix! - The H+ ions on the other side of the membrane “pull” the OH- group and charged ATP4- molecules through the ADP / ATP antiporter and the phosphate transporter!

- This enables a co-exchange to bring ADP and free phosphate into the matrix, through the same transporters!

- This yields the final ATP count therefore finishing the turning of glucose into energy!

Mechanisms for recycling excess amino acids into carbon skeletons and energy!

- Most amino acids produced from old proteins in the cell (skin and others) are used to create new proteins. !

- However, excess amino acids must be metabolised! - Amino acid catabolism (break down of amino acids) is mainly done in the liver.! - Amino acids can be converted to new protein, nitrogenous compounds of use to the body, or urea!

- This also means the liver is the main producer of urea! - Its in the liver that amino acids turn into ketone bodies, glucose or urea! - The produced urea is then shuttled Into the blood to the kidneys where it leaves as urine.!

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- The glucose and ketone bodies are released to the blood to maintain cellular energy levels!

- Ketone bodies are able to transit across the blood-brain barrier to keep neurons alive in starvation!

- Note that the brain cannot use anything other than glucose as their ingredient and it cannot use fatty acids due to blood brain barrier. !

- The first step of amino acid catabolism is transamination which is the transfer of an amino group from donor to acceptor!

- This makes sure that ammonia levels are regulated and that ammonia isn’t free as it is highly toxic. !

- Alpha-ketoglutarate, one of the TCA intermediates, is an amino group acceptor and takes in the amino group.!

- This is catalysed by the enzyme aminotransferase! - This reaction yields glutamate and the skeleton of the amino acid behind also known as alpha keto acid!

- Glutamate dehydrogenase then removes the amine group from glutamate which reacts with water to form an ammonium ion.!

- Some ammonium is converted to key nitrogen-containing compounds like nucleotides, carnitine, creotine, melatonin and histamine. (HCCMN)!

- The excess ammonium is discarded through the urea cycle! - Urea is less toxic and water soluble.! - This skeleton yielded with glutamate will then go down in one of two ways depending on their side chain (R group)!

- The glucogenic amino acid skeletons will turn into pyruvate and oxaloacetate.! - Pyruvate turns into oxaloacetate in the first step of gluconeogenesis so these are feed into gluconeogenesis, hence the name. !

- All amino acids except lysine and leucine are glucogenic ! - Lysine and Leucine are ketogenic amino acids. ! - Ketogenic amino acids have their skeletons turned into acetyl-CoA or acetoacetyl coA which give rise to ketone bodies or are feed into the TCA cycle and lipid metabolism. !

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- Five amino acids are both ketogenic and glucogenic, these are Phenylalanine, Isoleucine, Threonine, Tryptophan and Tyrosine !

- Amonia acid carbon skeletons can also become many different intermediates such as alpha ketoglutarate, fumrate, succinyl-coA and the ones already mentioned!

- Therefore, metabolically speaking, glucogenic amino acids can be used to make glucose!

- Ketogenic amino acids can’t be used to make glucose as humans cannot turn acetyl-coA into glucose!

- Therefore, ketogenic amino acids can only be used for energy gain once fed into the citric acid cycle and used to keep the brain alive when in starvation mood. !

Urea Cycle!

- Excess nitrogen needs to be eliminated from the body! - Urea is a convenient molecule for excretion! - It is less toxic than ammonia, water soluble, has no pH effect, transports 2 nitrogen atoms and has low residual energy!

- It is excreted in urine! - The urea cycle is restricted to the liver! - The urea cycle combines two amino groups, one from NH4+ and one from the amino acid aspartate, with a carbon atom from CO2 to form urea!

- The energy cost is four high energy phosphate bounds ! - It happens in five main steps! - Overview: Ammonia + Aspartate - Urea + Fumarate! - The first step in the urea cycle is the combination of CO2, ammonium ion and H2O to form carbamoyl phosphate.!

- This is done by carbomyl synthethase.! - It occurs in the mitochondrial matrix! - The CO2 is collected in the bicarbonate ion form! - Carbomyl phosphate then binds to ornithine ! 7

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- This yields citrulline! - This happens in the mitochondria! - The next steps occur in the cytosol! - A condensation reaction occurs between the amino group in aspartate and the carbonyl group of citrulline !

- This yields argininosuccinate! - Argininosuccinate is then cleaved into fumarate and arginine! - Arginine is hydrolysed and yields urea and ornithine! - The ornithine is then brought back into the mitochondria and the cycle begins again!

- It’s an efficient cycle! - Although it consumes 3 ATP molecules, reactions related to the urea cycle yield 2 NADH per cycle which can be fed into the electron transfer chain and acquire new ATP, 5 ATPs on average!

- Therefore it produces more energy than the one it uses! - Regulation wise, carbamoyl phosphate synthethase is allosterically activated by the N terminal of the acetylglutamic acid.!

- The abundance of acetylglutamic acid is a marker of cellular levels of glutamate and arginine!

- The remaining enzymes are controlled by the concentration of their respective substrates!

- Therefore the urea cycle accelerates when there’s lots of free amino acids in the cell!

- Disease wise, generally speaking, derive from defence in enzymes or the associated transporters which results in the build up of intermediates of the cycle or excess ammonia levels in the blood (coined hyperammonaemia)!

- Ammonia is particularly toxic to the brain meaning it’s a dangerous condition that may led to encephalophaty and death!

- Primary hyperammonaemia is caused by mutations in the enzymes ! - Secondary hyperammonaemia is caused by mutations in metabolic pathways linked to the urea cycle!

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- The most common primary hyperammonaemia is the X-linked condition ornithine transcarbamylase deficiency !

- Examples of secondary hyperammonaemias are propionic acidaemia and methylmalonic acidaemia!

The alanine-glucose cycle!

- The glucose-alanine cycle performs a very similar function to the Cori Cycle ! - The glucose-alanine cycle is used to shuttle pyruvate and ammonium from muscle tissues to the liver, for production of glucose and urea!

- The Cori cycle turns the lactic acid from the muscles into glucose by bringing it into the liver!

- Instead, in the glucose-alanine, pyruvate won’t be turned into lactate but into alanine!

- The alanine is released into the blood, where it travels to the liver to be converted into urea and pyruvate!

- The pyruvate is used as substrate for gluconeogenesis ! - This raises blood levels! - Some NH4+ is also sent from the muscles in the process!

Clinical significance of disorders of protein metabolism!

- Transaminase have useful diagnostic functions! - Some are tissue specific and are released into the blood when there’s tissue damage!

- Alanine transaminase (ALT) is expressed almost exclusively by the liver, so elevated levels suggest that the patient is suffering from liver damage!

- Aspartate transaminase (AST) is expressed in the liver but also the heart, kidneys, blood red cells and muscles making it less specific.!

- The ratio of ALT/AST is therefore considered an adequate marker of liver damage! - Urine should contain low amounts of protein in a healthy individual! - High levels of protein might indicate kidney damage!

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- Proteins are too large to pass through the glomeruli of the kidney from the blood to the urine!

- High protein levels are also known as proteinuria! - However, the most common cause is diabetes, since long-term exposure to high blood glucose can lead to damage to the glomerular filtration barrier (GFB) - this is called diabetic nephropathy !

- Eventually, the GFB becomes permeable to blood proteins, leading to proteinuria ! - If severe, the loss of blood proteins can lead to oedema! Major classes of hormones!

- Peptide/proteins: water soluble, short or long chains of amino acids! - Examples include insulin, oxytocin and human growth hormone! - Generally act on cell surface receptors! - Amines: modified amino acids, water or lipid soluble! - These are generated from the structural modification of amino acids! - Some are water soluble or lipid soluble ! - Examples include adrenaline (water soluble) and thyroxine (lipid soluble) and melatonin!

- Catecholamines are a significant subgroup of the amine hormones, derived from tyrosine !

- Examples include adrenaline, noradrenaline and dopamine! - They are comprised of an amine side-group attached to a catechol group! - Steroids: modified cholesterol molecules, lipid soluble! - Steroid hormones are based on cholesterol! - As they are small and lipophilic, they diffuse easily across the cell membrane! - Therefore they act on intracellular receptors! - Examples include cholesterol and testosterone! - Eicosanoids: modified fatty acids, water, or lipid soluble! - Generally generated by the modification of PUFA arachidonic acid (C20:4)!

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- There are many types which are regularly soluble on water or lipids depending on how oxidised they are.!

- They may therefore act on specific receptors on the cell surface, or on cytosolic (intracellular) receptors!

- Examples include prostaglandings and leukotrienes! Hormone receptors and signal transduction!

- Hormones are used to exert diverse regulatory effects on various target tissues. ! - They’re used to regulate various functions such as ! - Digestion! - Metabolism! - Respiration! - Growth and development! - Tissue function! - Sensory perception! - Sleep! - Lactation! - Stress! - Reproduction! - Mood! - Hormone signalling can trigger short or long lasting effects! - Testosterone can cause life-long developmental changes by directing cellular differentiation during development!

- Prostaglandin triggers inflammation within minutes! - Adrenaline enables a flight or flight response to danger within seconds! - Most hormones are produced by endocrine organs.! - Exocrine glands secret their products through a duct onto an epithelial cell surface (salivary, sweat, mammary and sebaceous glands)!

- By contrast, endocrine tissues secret hormones directly into the blood stream!

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- Examples include pineal gland (melatonic), pituitary gland (thyroid stimulating hormone), thyroid gland (thyroxin), thymus (thymosin), adrenal gland (adrenaline, cortisol), pancreas (insulin, glucagon), ovary (oestrogen and progesterone) and testis (testosterone).!

- Hormones can also act locally in autocrine and paracrine modes! - Although most hormones are produced by endocrine tissues, a small number of hormones (eicosanoids and cytokines) can be produced by diverse cells!

- These hormones often act only locally, on the same cell they were produced on (autocrine signalling) or on nearby cells (paracrine signalling)!

- Hormones may be formed as inactive pro-hormones initially and activated by various signals !

- Tropic hormones regulate the production of other hormones and most are produced and secreted by the anterior pituitary.!

- These are considered master hormones as they regulate various hormones.! - They also control specific hormone signalling “axes”. ! - These are:! - Hypothalamic-pituitary-adrenal (HPA) axis ! - Hypothalamic-pituitary-gonadal (HPG) axis! - Hypothalamic-pituitary-thyroid (HPT) axis! - Homeostasis is the process of keeping things within the normal range.! - Hormones play a huge role in homeostais.! - Homeostasis often involves negative feedback pathways. ! - The hormone biosynthesis and secretion is often regulated by negative feedback control!
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