Amino acid metabolism - Summary Biochemistry PDF

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Notes on amino acid metabolism...

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Amino acid metabolism     

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Surplus in amino acids needs to be broken down as they cannot be stored Non essential amino acids can be made, which is around 10/11 of the 20 standard amino acids Some non essential amino acids may become essential in certain physiological or pathological states o Essential amino acids- PVT TIM HALL Amino acid metabolism accounts for 10-15% of daily energy production but can be increased in cases of diseases/starvation Overview of protein metabolism: o Average 70kg person contains approximately 20% protein o 2% turned over every day i.e. broken down and resynthesized o 70% AAs for new protein synthesis recycled from protein breakdown o 25% used for protein synthesis to then synthesise into AA derivatives and other N containing compounds Nitrogen balance refers to the state where amount of nitrogen consumed is matched by the amount excreted o We may have a negative nitrogen balance where more nitrogen is excreted than consumed:  More protein breakdown than synthesis  Starvation  Cachexia  Dietary deficiency of essential amino acids o Or we can have a positive nitrogen balance  More protein synthesis takes place than breakdown  Growing children  Pregnancy (the mother would have to increase consumption of proteins or supplements to help the foetus grow)

Amino acid degradation  Amino group is separated from the carbon skeleton- deamination  Carbon skeleton may be reoxidised to produce energy or recycled  Removal of nitrogen from amino acids is a 2 step process o Step 1: transamination with a αketoglutarate to form glutamate and a new keto-acid o Step 2: glutamate is deaminated through oxidative process involving NAD+  α-keto acids are the equivalent to the carbon skeletons of the amino acids o Common pairings include: alanine/pyruvate, aspartate/oxaloacetate, glutamate/ αketoglutarate  Transamination o Transaminase (aka aminotransferase) enzymes catalyse the transfer of an alpha amino group from an amino acid to an alpha keto acid o The amino donor becomes an alpha keto acid while the amino acceptor becomes an amino acid o All aminotransferases utilize PLP (pyridoxal phosphate, B group vitamin as a cofactor) o Most transaminases have a preference for alpha ketoglutarate or oxaloacetate o Important interface between amino acid metabolism and energy metabolism  Oxaloacetate and alpha ketoglutarate are intermediates in the TCA cycle  Oxaloacetate and pyruvate are intermediates or precursors in gluconeogenesis

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Oxidative deamination of glutarate

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Urea cycle  

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o Reaction is catalyzed by glutamate dehydrogenase o Reaction is fully reversible o Takes place in the mitochondrial matric or liver, muscle and kidneys o NH4+ is formed o The reaction is allosterically regulated depending on the ATP/ADP ratio  A low ATP/ADP ratio favours the oxidative deamination process Glucogenic and ketogenic amino acids o Glucogenic amino acids are those whose C skeletons are converted to intermediates which can lead to net glucose synthesis o Ketogenic amino acids are those whose C skeletons are converted to intermediates which can lead to the synthesis of fatty acids and ketone bodies o Several amino acids are both glucogenic and ketogenic (PITTT- phenylalanine, isoleucine, threonine, tryptophan and tyrosine) Fate of the ammonium ion o NH4+ is toxic if allowed to accumulate o Aquatic animals excrete directly, birds & reptiles excrete in the form of uric acid, terrestrial vertebrates excrete in the form of urea o Some NH4+ is utilized in biosynthesis of nitrogen containing compounds such as other amino acids or purines o The C atom in urea is highly oxidised so it is only excreted after most of the available energy has been extracted Ammonia is transported to the liver as glutamate and glutamine o Extrahepatic tissues can break down amino acids but cannot process the amino groups- UREA CYCLE TAKES PLACE ONLY IN THE LIVER o Excess ammonia in tissues is converted to glutamate (glutamate dehydrogenase) and glutamine (glutamine synthetase) o Glutamate and glutamine are taken up by the liver and NH4+ is generated  Glutamine is converted to glutamate using the enzyme glutaminase  NH4+ is generated from glutamate using the enzyme glutamate dehydrogenase Glucose-alanine cycle/ Cahill cycle o Series of reactions in which amino groups and carbons from the muscle are transported to the liver (cycling of nutrients between skeletal muscle and the liver) o When muscles degrade amino acids, the resulting amino group is transaminated to pyruvate to form alanine o Alanine is shuttled to the liver where nitrogen enters the urea cycle and pyruvate is used gluconeogenesis to make glucose Occurs in the liver- some reactions take place in the mitochondrial matrix, some in the cytosol Mitochondrial phase: o First nitrogen acquiring reaction is the synthesis of carbamoyl phosphate o Catalysed by carbamoyl phosphate synthetase o 2 ATP consumed per carbamoyl phosphate formed o Citrulline is formed from ornithine and carbamoyl phosphate o This reaction is catalyzed by ornithine transcarbamoylase Cytosolic phase: o Second amino group enters the cycle as aspartate o The reaction between citrulline and aspartate to form arginine succinate is catalyzed by argininosuccinate synthetase o Fumarate is released as arginine is formed from argininosuccinate, catalyzed by argininosuccinase o Urea is released as arginine is converted to ornithine (water + arginine  ornithine) o Ornithine then enters the mitochondrial matrix where it combines with carbamoyl phosphate and the cycle begins again

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Regulation of carbamoyl phosphate synthetase (CPS) o CPS is allosterically activated by N-acetylglutamate (NAG)- the enzyme is inactive in absence of NAG o When there are high levels of glutamate, NAG is synthesized from glutamate and acetyl-CoA o It signals that there are high levels of free amino acids and the need to upregulate the urea cycle is necessary Urea cycle disorders o Enzymatic deficiencies o Potentially fatal because there is no alternative pathway for urea synthesis o Leads to hyperammonia which leads to acid/base disturbances & encephalopathy

Phenylketonuria (PKU)  Deficiency of phenylalanine hydroxylase, leading to phenylalanine accumulation in the blood  Accumulation leads to impaired brain development and function  Aspartame (sweetener) is made primarily from phenylalanine so people with PKU cannot consume aspartame as it acts as a poison  Tyrosine is normally synthesized by phenylalanine hydroxylase  Those with PKU have a lifelong dietary restriction of phenylalanine and also require tyrosine supplementation Maple-syrup urine disease  So called due to the characteristic urine odour  Mutations in various genes for protein (BCKDH) needed to break down certain amino acids  People with the condition cannot break down the amino acids leucine, isoleucine and valine (they eventually accumulate in the blood)  These enzymes are branched chain amino acids  Toxic to the brain and other organs Regulation of amino acid metabolism  2 key control points: o Glutamate dehydrogenase (high levels of ADP stimulate the production of NH4+) o Glutamine synthetase (glutamate + ammonia  glutamate)  Enzyme is subject to cumulative feedback inhibition by at least 8 different regulators (nitrogen sensory)  When all present at high levels, the enzyme is fully repressed)  Covalent modification of GS  GS is a key enzyme in controlling flow of nitrogen into biological molecules as glutamine serves as amino group donor for synthesis of many amino acids, nucleotides, amino sugars etc.)  Both enzymes are subject to allosteric regulation...