Amino Acid Metabolism.pdf

Amino Acid Metabolism Overview  Nitrogen enters the body by consuming proteins  It leaves the body as urea and uric acid  Free amino acids are present in the cells, blood and extracellular fluids  Amino acids are needed for the synthesis of proteins and other biomolecules  Excess amino acids...

Amino Acid Metabolism Overview  Nitrogen enters the body by consuming proteins  It leaves the body as urea and uric acid  Free amino acids are present in the cells, blood and extracellular fluids  Amino acids are needed for the synthesis of proteins and other biomolecules  Excess amino acids cannot be stored  The excess is used as metabolic fuel or excreted Nitrogen Excretion  Amino acids can be excreted in three different forms depending on the life form Animal type Nitrogen form Ammonotelic e.g. fish, amphibian ammonia Ureotelic e.g. humans, shark urea Uricotelic e.g. reptiles, birds uric acid  In ureotelic animals , 95 % of nitrogen is excreted in the urine and 5 % is excreted in the faeces Amino Acid Metabolism  In order for amino acids to be used as fuel, the amino group (-NH2) must first be detached from the structure (transamination) Transamination  Transamination occurs in the cytosol of the hepatocytes (liver cells)  The amino group is transferred from an amino acid to α-ketoglutarate forming an α-keto acid (derived from the amino acid) and glutamate  Therefore α-ketoglutarate is the amino group acceptor and the amino acid is the amino group donor  Glutamate is the new amino acid formed in the process  Transamination basically collects the amino group of the amino acids and convert them to one form of amino acid i.e. glutamate Transamination  All amino acids participate in transamination except lysine and threonine  Lysine and threonine lose their amino group by deamination. In this case the amino group that was removed is metabolized in the liver forming ammonia  Transamination is a reversible reaction and is catalyzed by an aminotransferase /transaminase enzyme. This enzyme is found in the cytosol and mitochondria  The cofactor pyridoxal phosphate is required for enzyme activity Transamination  The enzyme is specific for the amino acid, e.g. alanine transaminase or alanine aminotransferase catalyses the transamination of alanine  Aspartate aminotransferase disobeys the rule of transamination, i.e. the enzyme does not catalyze the transfer of the amino group to form glutamate  Instead this enzyme transfers the amino group from glutamate to oxaloacetate forming aspartate (source of nitrogen for the urea cycle)  In other words glutamate is not formed in this transamination reaction Transamination using oxaloacetate as the amino group acceptor AST – aspartate aminotransferase http://themedicalbiochemistrypage.org/images/ast-reaction.jpg Transamination  The glutamate that is formed during transamination can be used as an amino group donor for the synthesis of nonessential amino acids  Glutamate is transferred from the cytosol to the mitochondria where it undergoes deamination Oxidative Deamination  Oxidative deamination releases the amino group from glutamate (the amino acid typically formed during transamination)  Glutamate is the only amino acid capable of undergoing rapid deamination  The amino group is released as ammonia  The reaction is catalyzed by glutamate dehydrogenase and occurs in the liver and kidneys  The glutamate dehydrogenase is found only in the mitochondrial matrix  The enzyme is able to use either NAD+ or NADP+ as coenzymes Diagram showing transamination and oxidative deamination http://www.bmb.leeds.ac.uk/illingworth/bioc1010/image008.gif Oxidative Deamination  The amino group that is removed from glutamate is used to form ammonia (NH3)  The ammonia is then used in the biosynthesis of amino acids, nucleotides and biological amines  Excess ammonia is toxic to animal tissues. The high concentration is referred to as hyperammonemia  Hyperammonemia can cause retardation, mental disorder, coma and even death Oxidative Deamination  Glutamine and Alanine transport ammonia to the liver or kidneys  The conversion of ammonia to a non toxic form occurs in these organs  In the liver - ammonia is converted to urea via the urea cycle  In the kidneys - ammonia is excreted directly or converted to urea or uric acid and excreted Sources of Ammonia Some sources of ammonia include :(a) Amino acids (b) Glutamine – the reactions occur in the kidneys and intestines (c) Bacterial action in the intestines (d) Amines obtained from the diet and monoamines found in hormones and neurotransmitters (e) From the catabolism of purines and pyrimidines Regulation of Ammonia  The concentration of ammonia can be kept at low concentrations by two main processes 1. Urea formation 2. Glutamine synthesis Urea Cycle  The urea cycle was the first cyclic metabolic pathway to be discovered  The reactions begin in the mitochondrial matrix and continues into the cytosol of the hepatocytes  It involves the conversion of ammonia into urea Urea Cycle http://edoc.hu-berlin.de/dissertationen/xie-jing-2003-12-15/HTML/xie_html_40c2fe82.png Urea Cycle  The overall reaction for the urea cycle is CO2 + NH3 + 3ATP + aspartate urea + fumarate + 2 ADP + AMP + 2 Pi + PPi + 3 H2O  Urea diffuses form the liver and is transported in the blood to the kidneys where it is excreted in the urine  It also diffuses from the blood into the intestines and is excreted in the faeces Urea Cycle  In forming the urea molecule, one of the nitrogen is obtained from free ammonia and the other is obtained from the amino acid aspartate which is formed via transamination  The carbon comes from carbon dioxide  Ornithine serves as a carrier of the carbon and nitrogen atoms. This molecule is an amino acid, however it is not a precursor of protein Diagram showing the link between TCA and the urea cycle http://www.homepages.hetnet.nl/~b1beukema/TCAUrea.gif Glutamine Synthesis  The synthesis of glutamine also helps to maintain low concentrations of ammonia in the blood  The reaction occurs in the muscle and liver  Glutamine is present in the highest concentration in plasma compared to other amino acids Hyperammonemia  A defect in urea cycle, liver disease and genetic disorders can result in hyperammonemia  Normal concentration of ammonia in adults: 11 – 32 µmol/L . The concentration can also go up as high as 1000 µmol/L  There exists 2 types of hyperammonemia, i.e. acquired and hereditary Acquired hyperammonemia  Acquired hyperammonemia occurs in persons with liver disease. These include viral hepatitis, ischemia and cirrhosis of the liver  Portal blood i.e. blood from the digestive organs enters the systemic circulation bypassing entry into the liver. This prevents the conversion of ammonia into urea Hereditary hyperammonemia  Hereditary hyperammonemia occurs in 1:30,000 live births  Ornithine transcarbamoylase deficiency is the most common disorder  The failure to synthesize urea leads to an increase in ammonia during the first weeks of birth resulting in mental retardation  Treatment for this disease includes (a) reducing the protein intake (b) drug therapy – compounds are administered that bind covalently to amino acids converting them to products that are excreted in the urine In-born Errors of Amino Acid Metabolism  Disorders which occur due to a defect in amino acid metabolism includes – (a) Phenylketonuria (PKU) – most common (b) Maple Syrup Urine Disease (MSUD) (c) Albinism (d) Homocystinuria (e) Alkaptonuria Phenylketonuria (PKU)  Individuals with PKU are unable to utilize the amino acid phenylalanine due to a deficiency in the enzyme phenylalanine hydroxylase  This results in an accumulation of phenylalanine, phenylpyruvate, phenyllactate and phenylacetate  The accumulation of these substances gives the urine a musty odour  Phenylalanine is an essential amino acid that is needed for the synthesis of tyrosine. This reaction is catalyzed by phenylalanine hydroxylase. Tyrosine is needed for the synthesis of melanin and tissue proteins Phenylketonuria (PKU)  PKU is a recessive inheritance, i.e. the genes are obtained from both parents. The disorder is more common in Caucasians and oriental births than in Blacks  In the blood phenylalanine concentration is normally 1 mg/100 mL  PKU individuals the concentration ranges form 6 – 80 mg/100 mL Phenylketonuria (PKU) - Clinical features  Clinical features of PKU include :- (a) mental retardation in children 1 – 4 years. Adults usually have a very low intelligence quotient (IQ) (b) hypopigmentation – light hair colour and skin pigmentation (c) Epilepsy (d) hyperactivity Phenylketonuria (PKU) - treatment  Treatment for PKU includes regulating the amount of phenylalanine taken in the diet  Remember that phenylalanine is an essential amino acid. It is therefore needed in the diet as the body is unable to synthesize this amino acid Albinism  A group of conditions where the defect in tyrosine metabolism will result in a deficiency in the production of melanin  This results in partial or full absence of the pigment in the eye, skin and hair  The disease may be inherited by the following mode autosomal recessive (primary mode), autosomal dominant, X linked Types of Albinism  Different gene defects characterize the numerous types of albinism. Types of albinism include:  Oculocutaneous albinism (OCA)…OCA affects the skin, hair, and eyes. There are several subtypes of OCA:  OCA1 - OCA1 is due to a defect in the tyrosinase enzyme. There are two subtypes of OCA1:  OCA1a. People with OCA1a have a complete absence of melanin. People with this subtype have white hair, very pale skin, and light eyes.  OCA1b. People with OCA1b produce some melanin. They have lightcolored skin, hair, and eyes. Their coloring may increase as they age.  OCA2 is less severe than OCA1. It’s due to a defect in the OCA2 gene that results in reduced melanin production.  People with OCA2 are born with light coloring and skin. Their hair may be yellow, blond, or light brown. OCA2 is most common in people of African descent and Native Americans  OCA3 - OCA3 is a defect in the TYRP1 gene. It usually affects people with dark skin, particularly black South Africans. People with OCA3 have reddish-brown skin, reddish hair, and hazel or brown eyes  OCA4 - OCA4 is due to a defect in the SLC45A2 protein. It results in a minimal production of melanin and commonly appears in people of East Asian descent. People with OCA4 have symptoms similar to those in people with OCA2 Albinism– Clinical features  Clinical features of albinism include :a) Hypopigmentation b) strabismus (crossed eyes) c) photophobia (sensitivity to light) d) nystagmus (involuntary rapid eye movements) e) impaired vision or blindness f) Astigmatism They are at increased risk for cancer