Amino Acid Metabolism | Anatomy2Medicine
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Amino Acid Metabolism

    • Synthesis of amino acids
      • Messenger RNA contains codons for 20 amino acids
      • Eleven of these amino acids can be synthesized in the body.
        • The carbon skeletons of 10 of these amino acids can be derived from glucose.
        • These 10 are serine, glycine, cysteine, alanine, glutamic acid, glutamine, aspartic acid, asparagine, proline, and arginine
        • tyrosine is derived from phenylalanine.
      • The essential amino acids derived from diet are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
      • Amino acids derived from intermediates of glycolysis

 

  • Intermediates of glycolysis serve as precursors for serine,glycine,cysteine,and alanine
  • Serine can be synthesized from the glycolytic intermediate 3-phosphoglycerate, which is oxidized, transaminated by glutamate, and dephosphorylated.

 

          • Glycine and cysteine can be derived from serine.
            • Glycine can be produced from serine by a reaction in which a methylene group is transferred to tetrahydrofolate (FH4).
            • Cysteine derives its carbon and nitrogen from serine
            • The essential amino acid methionine supplies the sulfur.
          • Alanine can be derived by transamination of pyruvate.
      • Amino acids derived from TCA cycle intermediates( MCQ)
        • Aspartate can be derived from oxaloacetate by transamination.
        • Asparagine is produced from aspartate by amidation.
        • Glutamate is derived from a-ketoglutarate by the addition of NH4+ via the glutamate dehydrogenase reaction or by transamination.
        • Glutamine, proline, and arginine can be derived from glutamate
          • Glutamine is produced by amidation of glutamate.
          • Proline and arginine can be derived from glutamate semialdehyde, which is formed by reduction of glutamate.

 

  • Proline can be produced by cyclization of glutamate semialdehyde.

 

            • Arginine, via three reactions of the urea cycle, can be derived from ornithine, which is produced by transamination of glutamate semialdehyde.
      • Tyrosine
        • the 11th nonessential amino acid
        • synthesized by hydroxylation of the essential amino acid phenylalanine
        • reaction requires tetrahydrobiopterin.
    • Degradation of amino acids
      • When the carbon skeletons of amino acids are degraded, the major products are pyruvate, intermediates of the TCA cycle, acetyl CoA, and acetoacetate
        • Amino acids that form pyruvate or intermediates of the TCA cycle in the liver are glucogenic (or gluconeogenic); that is, they provide carbon for the synthesis of glucose
        • Amino acids that form acetyl CoA or acetoacetate are ketogenic; that is, they form ketone bodies

 

  • Some amino acids (isoleucine, tryptophan, phenylalanine, and tyrosine) are both glu- cogenic and ketogenic. (MCQ)

 

      • Amino acids that are converted to pyruvate
        • The amino acids that are synthesized from intermediates of glycolysis (serine, glycine, cysteine, and alanine) are degraded to form pyruvate.
        • Serine
          • is converted to 2-phosphoglycerate, an intermediate of glycolysis
          • is converted directly to pyruvate and NH4+ by serine dehydratase, which is an enzyme that requires PLP.

 

  • Glycine
  • in a reversal of the reaction used for its synthesis, reacts with methylene FH4 to form serine.

 

          • Glycine also reacts with FH4 and NAD+ to produce CO2 and NH4+.
          • Glycine can be converted to glyoxylate, which can be oxidized to CO2 and H2O, or converted to oxalate.
        • Cysteine forms pyruvate
          • Its sulfur, which was derived from methionine, is converted to sulfuric acid (H2SO4), which is excreted by the kidneys.
        • Alanine can be transaminated to pyruvate.
      • Amino acids that are converted to intermediates of the TCA cycle

 

  • Carbons from four groups of amino acids form the TCA cycle intermediates alpha-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate.

 

        • Amino acids that form alpha-ketoglutarate
          • Glutamate can be deaminated by glutamate dehydrogenase or transaminated to form alpha-ketoglutarate.
            • Glutamine is converted by glutaminase to glutamate with the release of its amide nitrogen as NH4+.
            • Proline is oxidized so that its ring opens, forming glutamate semialdehyde, which is reduced to glutamate.
            • Arginine is cleaved by arginase in the liver to form urea and ornithine
              • Ornithine is transaminated to glutamate semialdehyde, which is oxidized to glutamate.
            • Histidine is converted to formiminoglutamate (FIGLU).
              • The formimino group is transferred to FH4, and the remaining five carbons form glutamate.
      • Amino acids that form succinyl CoA
        • Four amino acids (threonine, methionine, valine, and isoleucine) are converted to propionyl CoA.
        • Propionyl CoA is carboxylated in a biotin-requiring reaction to form methylmalonyl CoA.
        • Methylmalonyl CoA is rearranged to form succinyl CoA in a reaction that requires vitamin B12.
        • Threonine
          • is converted by a dehydratase to NH4+ and a-ketobutyrate, which is oxidatively decarboxylated to propionyl CoA
          • In a different set of reactions, threonine is converted to glycine and acetyl CoA.
        • Methionine provides methyl groups for the synthesis of various compounds
          • sulfur is incorporated into cysteine
          • remaining carbons form succinyl CoA.
          • Methionine and ATP form S-adenosylmethionine (SAM), which donates a methyl group and forms homocysteine.
        • Homocysteine is reconverted to methionine by accepting a methyl group from the FH4 pool via vitamin B12.
          • Homocysteine can also react with serine to form cystathionine
          • The cleavage of cystathionine produces cysteine, NH4+, and a-ketobutyrate, which is converted to propionyl CoA.
        • Valine and isoleucine, two of the three branched-chain amino acids, form succinyl CoA
          • Branched-chain alpha-ketoacid dehydrogenase complex
            • Degradation of all three branched-chain amino acids begins with a transamination, followed by an oxidative decarboxylation catalyzed by the branched-chain a-ketoacid dehydrogenase complex
            • This enzyme, like pyruvate dehydrogenase and a-ketoglutarate dehydrogenase, requires thiamine pyrophosphate, lipoic acid, CoA, fla- vin adenine dinucleotide (FAD), and NAD+.
          • Valine
            • Eventually converted to succinyl CoA via propionyl CoA and methyl malonyl CoA.
          • Isoleucine also forms succinyl CoA after two of its carbons are released as acetyl CoA.
      • Amino acids that form fumarate
        • Three amino acids (phenylalanine, tyrosine, and aspartate) are converted to fumarate
        • Phenylalanine
          • converted to tyrosine by phenylalanine hydroxylase in a reaction requiring tetrahydrobiopterin and O2.
        • Tyrosine
          • obtained from the diet or by hydroxylation of phenylalanine
          • converted to homogentisic acid.
          • The aromatic ring is opened and cleaved, forming fumarate and acetoacetate.
        • Aspartate
          • converted to fumarate through reactions of the urea cycle and the purine nucleotide cycle.
          • Aspartate reacts with IMP to form AMP and fumarate in the purine nucleotide cycle.
      • Amino acids that form oxaloacetate
        • Aspartate is transaminated to form oxaloacetate.
        • Asparagine loses its amide nitrogen as NH4+, forming aspartate in a reaction catalyzed by asparaginase.
      • Amino acids that are converted to acetyl Co A or acetoacetate
        • Four amino acids (lysine,threonine,isoleucine,and tryptophan) can form acetyl CoA
        • Phenylalanine and tyrosine form acetoacetate.

 

  • Leucine is degraded to form both acetyl CoA and acetoacetate.

 

Applied aspects

    • Type I primary oxaluria
      • results from the absence of a transaminase, which converts glyoxylate to glycine
      • resulting in renal failure due to excess oxalate in the kidney.
    • Histidinemia
      • histidase, which converts histidine to urocanate, is defective.
      • associated with mental retardation
    • hereditary deficiency of methylmalonyl CoA mutase
      • results in failure to thrive, vomiting, dehydration, developmental delay, and seizures.
      • Accumulation of propionyl CoA, a substrate for the TCA cycle enzyme citrate synthase, leading to the condensation of propionyl CoA with oxaloacetate, which leads to the accumulation of the TCA toxin, methyl citrate.

 

  • Homocystinuria

 

      • most often due to a defect in cystathionine beta-synthase,
      • lead to increased homocysteine and methionine.

 

  • Patients present with dislocation of the lens, mental retardation, and skeletal and neurologic abnormalities.
  • Maple syrup urine disease

 

      • enzyme complex that decarboxylates the transamination products of the branched-chain amino acids (the a-ketoacid dehydrogenase) is defective
      • Valine, isoleucine, and leucine accumulate.
      • Urine has the odor of maple syrup.
      • Mental retardation and poor myelination of nerves occur.

 

  • phenylketonuria (PKU

 

      • conversion of phenylalanine to tyrosine is defective
      • defect in phenylalanine hydroxylase
      • A variant, nonclassic PKU
        • result of a defective enzyme in tetrahydrobiopterin synthesis.
      • Phenylalanine accumulates in both disorders and is converted to compounds such as the phenylketones, which give the urine a musty odor
      • Mental retardation occurs.
      • PKU is treated by restriction of phenylalanine in the diet.
    • Alkaptonuria
      • homogentisic acid, which is a product of phenylalanine and tyrosine metabolism, accumulates
      • homogentisate oxidase is defective.
      • Homogentisic acid auto-oxidizes, and the products polymerize, forming dark-colored pigments, which accumulate in various tissues
      • associated with a degenerative arthritis.

 

  • Isovaleric acidemia

 

    • results from a defect in isovaleryl CoA dehydrogenase,
    • prevent the degradation of isovaleryl CoA during the degradation of leucine.
    • The defect results in neuromuscular irritability and mental retardation
    • The patient has a distinctive odor of ‘‘sweaty feet.’’
    • Limiting the intake of leucine helps limit the progression of symptoms.

 

Topic- Urea Cycle

Addition and removal of amino acid nitrogen

    • Transamination reactions
      • Transamination involves the transfer of an amino group from one amino acid (which is converted to its corresponding alpha-ketoacid) to an alpha-ketoacid (which is converted to its corresponding alpha-amino acid)
      • Glutamate and alpha-ketoglutarate are often involved in transamination reactions, serving as one of the amino acid/a-ketoacid pairs

 

  • Enzymes that catalyze transamination reactions are known as transaminases or aminotransferases.

 

      • Transamination reactions are readily reversible
      • Transamination can be used in the synthesis or the degradation of amino acids.
      • Most amino acids participate in transamination reactions.
        • Lysine is an exception; it is not transaminated. (MCQ)
      • Pyridoxal phosphate (PLP)
        • serves as the cofactor for transamination reactions. (MCQ)
        • PLP is derived from vitamin B6.
    • Removal of amino acid nitrogen as ammonia
    • A number of amino acids undergo reactions in which their nitrogen is released as ammonia (NH3) or ammonium ion (NH4+).

 

  • Glutamate dehydrogenase

 

      • catalyzes the oxidative deamination of glutamate
      • requires NAD or NADP.
      • Ammonium ion is released, and alpha-ketoglutarate is formed.
      • readily reversible

 

  • Histidine is deaminated by histidase to form NH4+ and urocanate.

 

    • Serine and threonine are deaminated by serine dehydratase,
      • requires PLP.
      • Serine is converted to pyruvate
      • threonine is converted to alpha-ketobutyrate
      • NH4+ is released.
    • The amide groups of glutamine and asparagine are released as ammonium ions by hydrolysis
      • Glutaminase converts glutamine to glutamate and NH4+.
      • Asparaginase converts asparagine to aspartate and NH4+.
    • The purine nucleotide cycle serves to release NH4+ from amino acids, particularly in muscle.
      • Glutamate collects nitrogen from other amino acids and transfers it to aspartate by a transamination reaction.
      • Aspartate reacts with inosine monophosphate (IMP) to form AMP and generate fumarate.
      • NH4+ is released from AMP, and IMP is reformed.
    • The role of glutamate
      • Glutamate provides nitrogen for synthesis of many amino acids.
      • NH4+ provides the nitrogen for amino acid synthesis by reacting with alpha-ketoglutarate to form glutamate in the glutamate dehydrogenase reaction.
      • Glutamate transfers nitrogen by transamination reactions to alpha-ketoacids to form their corresponding alpha-amino acids.
      • Glutamate plays a key role in removing nitrogen from amino acids.
      • a-Ketoglutarate collects nitrogen from other amino acids by means of transamination reactions, forming glutamate.
      • The nitrogen of glutamate is released as NH4+ via the glutamate dehydrogenase reaction
      • NH4+ and aspartate provide nitrogen for urea synthesis via the urea cycle. Aspartate obtains its nitrogen from glutamate by transamination of oxaloacetate.

 

  • Urea cycle

 

      • Transport of nitrogen to the liver
        • Ammonia is very toxic  to the CNS
        • The concentration of ammonia and ammonium ions in the blood is normally very low
        • Ammonia is in equilibrium with ammonium ion with a pKa of 9.3.

 

  • NH3 is freely diffusible across membranes, but at physiologic pH, the concentration of ammonia is 1/100 the concentration of the NH4+ ion

 

        • Ammonia travels to the liver from other tissues, mainly in the form of alanine and glutamine

 

  • It is released from amino acids in the liver by a series of transamination and deamination reactions.

 

        • Ammonia is also produced by bacteria in the gut and travels to the liver via the hepatic portal vein
        • Mechamism of action of  lactulose to treat Hyperammonemia
          • increasing bacterial assimilation of ammonia
          • reducing deamination of nitrogenous compounds
    • Reactions of the urea cycle
      • NH4+ and aspartate provide the nitrogen that is used to produce urea, and CO2 provides the carbon.
      • Ornithine serves as a carrier that is regenerated by the cycle.
      • Reaction 1: Carbamoyl phosphate is synthesized in the first reaction from NH4+, CO2, and two ATP  molecules.
        • In organic phosphate and two ADP molecules are also produced

 

  • Enzyme: carbamoyl phosphate synthetase I

 

        • located in mitochondria
        • activated by N-acetylglutamate (MCQ)

 

  • Reaction 2 :Ornithine reacts with carbamoyl phosphate to form citrulline

 

        • Inorganic phosphate is released
        • Enzyme:ornithine trans carbamoylase
        • found in mitochondria
        • The product,citrulline,is transported to the cytosol in exchange for ornithine.
      • Reaction 3: Citrulline combines with aspartate to form argininosuccinate
        • enzyme : argininosuccinate synthetase
        • reaction that is driven by the hydrolysis of ATP to AMP and inorganic pyrophosphate.
      • Reaction 4: Argininosuccinate is cleaved to form arginine and fumarate.
        • Enzyme:arginine succinate lyase
        • This reaction occurs in the cytosol.
        • The carbons of fumarate, which are derived from the aspartate added in reaction 3, can be converted to malate.
        • In the fasting state in the liver, malate can be converted to glucose or to oxaloacetate, which is transaminated to regenerate the aspartate required for reaction 3.

 

  • Reaction 5 :Arginine is cleaved, with the help of the enzyme, arginase, to form urea and regenerate ornithine.

 

        • Arginase
          • is located primarily in the liver
          • is inhibited by ornithine.
        • Urea passes into the blood and is excreted by the kidneys.
        • The urea excreted each day by a healthy adult (about 30 g) accounts for about 90% of the nitrogenous excretory products.
        • Ornithine is transported back into the mitochondrion (in exchange for citrulline), where it can be used for another round of the cycle.

 

  • When the cell requires additional ornithine,it is synthesized from glucose via glutamate

 

      • Arginine is a nonessential amino acid.
        • It is synthesized from glucose via ornithine and the first four reactions of the urea cycle.
  • Regulation of the urea cycle
    • N-Acetylglutamate is an activator of CPS I, the first enzyme of the urea cycle.
    • Arginine stimulates the synthesis of N-acetylglutamate from acetyl coenzyme A (CoA) and glutamate.
    • In liver ,enzymes of the urea cycle are induced if a high-protein diet is consumed for  4 days or more.
  • How is urea cycle and the tricarboxylic acid (TCA) cycle are linked
    • one of the urea nitrogen molecules is supplied to the urea cycle as aspartic acid, which is formed from the TCA cycle intermediate oxaloacetic acid.(MCQ)

 

 

  • Applied aspects

 

    • Hereditary deficiency of carbamoyl phosphate synthetase I (CPS I)
    • results in an inability for ammonia to be metabolized via the urea cycle.
      • Hyperammonemia leads to brain damage, coma, or death, without strict dietary control.
    • Deficiency of ornithine transcarbamoylase
      • an X-linked trait
      • results in similar neurologic sequelae as CPS I deficiency.

 

  • Citrullinemia

 

      • deficiency of the enzyme argininosuccinate synthetase

 

  • manifestations of this disease include lethargy, hypotonia, seizures, ataxia, and behavioral changes.
  • Argininosuccinate aciduria

 

    • deficiency of the enzyme argininosuccinate lyase in the urea cycle
    • results in hyperammonemia with grave effects on the CNS.
    • Unlike deficiencies of other enzymes in the urea cycle, arginase deficiency does not result in severe hyperammonemia. (MCQ)
    • The reason is twofold.
        • First, the formed arginine, containing two ‘‘waste’’ nitrogen molecules, can be excreted in the urine.

 

  • Second, there are two isozymes, and in the event that the predominant liver enzyme is dysfunctional, the peripheral isozyme is inducible, leading to adequate restoration of the pathway.

 

 

Topic –  CELL MEMBRANE

    • Membrane structure
      • Membranes are composed mainly of lipids and proteins
      • Membrane lipids
        • Phosphoglycerides are the major
        • sphingolipids
        • cholesterol
      • Phospholipids
        • form a bilayer,

 

  • hydrophilic head groups interact with water on both the extracellular and intracellular surfaces

 

        • hydrophobic fatty acyl chains in the central portion of the membrane.
      • Peripheral proteins are attached at the periphery of the membrane
      • Integral proteins span from one side of the membrane to the other.
      • Carbohydrates
        • attached to proteins and lipids on the exterior side of the cell membrane
        • They extend into the extracellular space.

 

  • Lipids and proteins

 

      • can diffuse laterally within the plane of the membrane.
      • Therefore, the membrane is termed ‘‘fluid mosaic.’’
  • Membrane function
    • Membranes serve as barriers that separate the contents of a cell from the external environment or the contents of individual organelles from the remainder of the cell.
    • The proteins in the cell membrane have many functions.
      • transport of substances across the membrane.
      • enzymes that catalyze biochemical reactions.
      • function as receptors that bind external ligands such as hormones or growth factors.
      • mediators that aid the ligand–receptor complex in triggering a sequence of events (e.g., G proteins) known as signal transduction;
        • second messengers (e.g., cAMP ) that alter metabolism are produced inside the cell.
  • cystic fibrosis transmembrane regulator (CFTR)
    • results in cystic fibrosis (CF)
    • a chloride ion channel found on cell membranes.
    • the most common mutation of which is the loss of a phenylalanine residue at position 508, known as the DF508 mutation