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Catabolism of proteins and aa nitrogen
• How the nitrogen of aa is converted to urea and the rare disorders that accompany defects in urea biosynthesis
• Normal condition- nitrogen intake match nitrogen excreted
• Positive nitrogen balance- an excess of ingested over excreted nitrogen- during growth and pregnancy
• Negative nitrogen balance – output exceeds intake- during surgery, advanced cancer or malnutrition
Oxidative degradation occur in 3 diff metabolic circumstances:
1)During normal synth and degradation of cellular protein- aa that are released from protein breakdown are not needed for new prot synthesis-degraded
2)Taking a protein rich diet- aa intake exceeds the body’s need for prot- degraded
3)During starvation or in uncontrolled DM – when carb cannot be utilized, proteins are used as fuel
• Under all this metabolic conditions- aa lose their amino groups to form α-ketoacids (the carbon skeleton of amino acids)
• The α-ketoacids undergo oxidation to CO2 and H20 and provide 3-4C for gluconeogenesis
Metabolic fates of amino groups
• Degradation of ingested proteins to aa occurs in gastrointestinal tract
• Entry of protein dietary will stimulate the hormone gastrin – will stimulate the production of HCl- kill most bacteria, denaturing agent for protein, unfolding globular proteins, and make internal peptide bonds more accessible to enzymatic hydrolysis
• Pepsin is activated to cleave the polypeptide to smaller peptide
Dietary protein is enzymatically degraded to amino acids
• Once protein are degraded to amino acids, aa are transported to liver- to remove the amino groups – by aminotransferases or transaminases
• The amino groups are transferred α-ketoglutarate- forming glutamate
Glutamate releases its amino group as ammonia in the liver
• Amino groups must be removed from glutamate for excretion
• In hepatocytes, glutamate is transported from cytosol to mitoch – undergoes oxidative deamination- cat by glutamate dehydrogenase produced NH4+
• NH4+ is transported by glutamine to liver to be secreted thru urea cycle
Excretion of excess nitrogen• Excess nitrogen – excreted in one of three forms: ammonia
(as ammonium ion), urea and uric acid
• Fish – excrete ammonia – protected by the toxic activity through excretion and rapid dilution by environment
• Terrestrial animals- excrete urea- water soluble compounds
• Birds- excrete uric acid – insoluble in water- to avoid excess weight
• High blood urea level as a consequence (not a cause) of impaired renal fx
Urea cycle• Central pathway in nitrogen metabolism- urea cycle
• Start with the reaction of ammonium ion and C02 to produce carbamoyl phosphate
• Step 1- Carbamoyl phosphate + ornithine →citrulline (carbamoyl phosphatase 1
• Citrulline + Nitrogen (2nd)→arginino succinate
• Arginino succinate → fumarate and arginine
• Arginine → urea and regenerate ornithin
• Fumarate enter the TCA cycle
Ammonia intoxication
• Ammonia produced by enteric bacteria and produced by tissues are rapidly cleared from circulation by the liver and converted to urea
• Ammonia is toxic to central nerveous system
• Ammonia levels may rise to toxic levels in impaired hepatic function – cirrhosis
• Ammonia is toxic to brain – reacts with α-ketoglutarate to form glutamate – depleted levels of α-ketoglutarate – impair fx of TCA cycle in neurons
• Mammals with genetic defects in any enzyme involved in urea formation cannot tolerate protein rich diet- as free ammonia cant be converted to urea- lead to hyperammonemia
• Protein free diet is not an option. Mammals are incapable of synthesizing all 20 amino acids, thus must come from diet
Ammonia intoxication
Amino acid catabolism
• Involve transferring the amino nitrogen to α-ketoglutarate to produce glutamate- leaving behind the carbon skeleton
• After removal of their amino groups, the carbon skeleton of aa undergo oxidation to compounds that can enter the TCA cycle
• In liver
The fate of carbon skeleton
• Glucogenic aa yields pyruvate or OAA on degradation -----> gluconeogenesis
• Ketogenic aa breaks down to acetyl-CoA or acetoacetyl-CoA- leading to the formation of ketone bodies
Six aa are degraded to pyruvate
• Alanine, tryptophan, cystein, serine, glycine, and threonine
• All are converted to pyruvate
• Pyruvate can either be converted to acetyl-CoA (Ketone bodies precursor)
• Or converted to OAA (gluconeogenesis)
Glycine degradation
• Can be degraded in 3 ways – only one yield pyruvate
1)Involve conversion of glycine to serine via catalysis of serine hydroxymethyl transferase. Serine is then converted to pyruvate
2) Glycine undergoes oxidative cleavage to CO2, NH4+ and a methylene group – catalysed by glycine cleavage enzyme (or glycine synthase)
• This pathway is critical in mammals
• Defects in glycine cleavage enzyme- lead to elevated serum of glycine – inhibit neurotransmitter- mental retardation
Glycine degradation
3) Conversion of glycine to glyoxylate by D-amino acid oxidase. Glyoxylate is further oxidized to oxalate
• Crystals of calcium oxalate account for 75% of all kidney stones
Glycine degradation
Ketogenic amino acid
• Phenylalanine, tyrosine, isoleucine, leucine, tryptophan, threonine, and lysine
• Breakdown of trp – precursor to synthesis NAD and NADP in animalsSerotonin – a neurotransmitter in vertebrate
Phenylalanine catabolism
• Phenylalanine- precursor for dopamin (a neurotransmitter) and hormones (norepinephrine and epinephrine)
• Breakdown of phenylalanine- catalysed by phenylalanine carboxylase
• Deficiency of this enzyme lead to phenylketoneuria (PKU) disease – due to elevated levels of phenylalanine
PKU• Defiency of phenylalanine carboxylase cause phenylalanine
undergoes transamination with pyruvate – yield phenylpyruvate –
• Accumulate in blood and tissues- excreted thru urine
• Other than being excreted as urine directly, some of phenylpyruvate are reduced to phenylacetate – give odor to urine – nurses have traditionally used to detect PKU in infants
• Accumulation of phenylalanine in early life impairs normal development of the brain- mental retardation
• Due to excess of phenylalanine competing with other aa for transport across the blood brain-barrier- deficit required metabolites
• Mental retardation can be prevented by rigid diet- provide only enough phenylalanine
The fate of branched amino acid
• Isoleucine, leucine, and valine
• Degraded only in extrahepatic tissues – oxidized as fuels in muscles, adipose, kidney
• Due to the presence of branched-chain α-ketoacid dehydrogenase complex- absent in liver
Maple syrup urine disease• Due to the defective branched-chain α-ketoacid
dehydrogenase complex-
• Lead to accumulation of leucine in blood- and excreted to urine – smell like maple syrup
• Untreated lead to abnormal development of the brain, mental retardation, and death in early infacy
• Treatment include limiting the intake of valine, isoleucine, and leucine