Amino Acid Oxidation and the Production of Urea

Ammonotelic animals

excrete amino nitrogen as ammonia

• most aquatic species

Ureotelic animals

excrete amino nitrogen primarily as urea

• most terrestrial animals

Uricotelic animals

excrete amino nitrogen as uric acid

• birds and reptiles

Gastrin

hormone secreted when dietary protein enters the stomach

• stimulates the secretion of HCl and pepsinogen

Pepsinogen

zymogen that is converted to active pepsin by autocatalytic cleavage at low pH

Pepsin

cleaves long polypeptide chains into a mixture of smaller peptides

Secretin

hormone secreted into the blood in response to low pH in the small intestine

• stimulates the pancreas to secrete bicarbonate into the small intestine

Cholecystokinin

hormone secreted into the blood in response to the arrival of peptides in the duodenum

Proteases cholecystokinin stimulates the pancreas to secrete

• trypsinogen is the zymogen of trypsin

• chymotrypsinogen is the zymogen of chymotrypsin

  • procarboxypeptides A and B are the zymogens of carboxypeptidases A and B

Enteropeptidase

a proteolytic enzyme that converts trypsinogen to trypsin

Trypsin

activates additional trypsinogen, chymotrypsinogen, the procarboxypeptidases, and proelastases

Pancreatic trypsin inhibitor

protein inhibitor that further protects the pancreas against self-digestion

Acute pancreatitis

caused by obstruction of the pathway by which pancreatic secretions enter the intestine

Aminotransferases (transaminases)

catalyze the removal of the α-amino groups

Transamination

transfer of the α-amino group to the α-carbon atom of α-ketoglutarate, yielding an α-keto acid analog of the aa

Pyridoxal phosphate (PLP)

the coenzyme form of pyridoxine or vitamin B6

PLP (aldehyde form)

accepts an amino group

Pyridoxamine phosphate (aminated form)

donates its amino group to an α-keto acid

L-glutamate dehydrogenase

catalyzes the oxidative deamination of glutamine to produce NH4+ and α-ketoglutarate

Transdeamination rxns

result from the combined action of an aminotransferase and glutamate dehydrogenase

Glutamine synthetase

catalyzes the combination of free ammonia w/ glutamate to yield glutamine

• requires ATP

• critical to transport toxic ammonia to the liver

Glutaminase

catalyzes the conversion of glutamine to glutamate and NH4+

Alanine aminotransferase

interconverts pyruvate and alanine via transamination w/ glutamate

Glucose-alanine cycle

pathway by which alanine carries ammonia and the carbon skeleton from pyruvate to the liver

• ammonia is excreted

• pyruvate is used to produce glucose, which is returned to the muscle

NA+-K+-2Cl- cotransporter 1 (NKCC1)

symporter that transpprts Na+, K+, and Cl-

Urea cycle

pathway by which the ammonia deposited in the mitochondria of hepatocytes is converted to urea

Carbomoyl phosphate synthetase I

catalyzes the formation of carbamoyl phosphate from NH4+ and CO2 (HCO3-)

• requires 2 ATP

• occurs in the mitochondrial matrix

Ornithine transcarboamoylase

catalyzes the formation of citrulline and Pi from ornithine and carbamoyl phosphate

Argininosuccinate synthetase

catalyzes the condensation of the amino group of aspartate and the ureido group of citrulline to form argininosuccinate

• requires 2 ATP

• uses a citrullyl-AMP intermediate

Argininosuccinase

catalyzes the reversible cleavage of argininosuccinate fo form arginine and fumarate

Arginase

Catalyzes the cleavage of arginine to form urea and ornithine

Aspartate-argininosucinate shunt

pathways linking the citric acid and urea cycles

• link the fates of the amino groups and the carbon skeletons of amino groups

N-acetylglutamate synthase

catalyzes the formation of N-acetylglutamate from acetyl-CoA from glutamate

N-acetylglutamate

allosterically activates carbamoyl phosphate synthetase I

Essential amino acids

amino acids that cannot be synthesized by humans and must be obtained in the diet

Amino Acid Catabolism’s 20 pathways’ major products

• pyruvate

• acetyl-CoA

• α-ketoglutarate

• succinyl-CoA

• fumarate

• oxaloacetate

Ketogenic amino acids

can yield ketone bodies in the liver

ex. phenylalanine, tyrosine, isoleucine, leucine, tryptophan, threonine, and lysine 

Glucogenic amino acids

can be converted to glucose and glycogen

ex. all amino acids except lysine and leucine

3 factors involved in one-carbon transfers

• biotin (transfers CO2)

• tetrahydrofolate (transfers intermediate oxidation states)

• S-adenosylmethionine (transfers methyl groups)

Tetrahydrofolate (H4 folate)

consists of substituted pterin (6- methylpterin), p-aminobenzoate and glutamate moieties

Folate

oxidized form of tetrahydrofolate

Pernicious anemia

observed in B12 deficiency disease

Megaloblastic anemia

observed in vitamin B12 deficiency

• decline in the production of mature erythrocytes

• appearance of immature precursor cells, or megaloblasts, in the bone marrow

• replacement of erythrocytes with a smaller number of abnormally large erythrocytes (macrocytes)

Tetrahydrobiopterin

cofactor of aa catabolism

• participates in oxidation rxns

Amino acids degraded to pyruvate:

• alanine

• tryptophan

• cysteine

• serine

• glycine

• threonine

Pyruvate is converted to:

• acetyl-CoA for oxidation via TCA

• oxaloacetate to enter gluconeogenesis

Serine dehydratase

catalyzes the conversion of serine to pyruvate

• removes both the β-hydroxyl and the α-amino groups of serine

• pyridoxal phosphate-dependent rxn

Serine hydroxymethyltransferase

catalyzes the enzymatic rxn addition of the hydroxymethyl group to glycine to yield serine

• requires tetrahydrofolate and pyridoxal phosphate

Glycine cleavage enzyme

catalyzes the reversible oxidative cleavage of glycine to CO2, NH4+, and a methylene group

• requires tetrahydrofolate

• enzymatic defects causes the formation of methylglyoxal, which modifies proteins and DNA

D-amino acid oxidase

catalyzes the conversion of glycine to glyoxylate, which is oxidized to oxalate

Amino acids degraded to acetyl-CoA via acetoacetyl-CoA

• lecine

• lysine

• phenylalanine

• tyrosine

• tryptophan

Amino acids degraded to acetyl-CoA directly

• isoleucine

• leucine

• threonine

• tryptophan

Phenylketonuria (PKU)

disease caused by a genetic defect in phenylalanine hydroxylase

• most common cause of elevated levels of phenylalanine in the blood

• treated with dietary intervention

Phenylalanine hydroxylase

the first enzyme in the catabolic pathway for phenylalanine

• requires the cofactor tetrahydrobiopterin

Dihydrobiopterin reductase

catalyzes the reduction of duhydrobiopterin to tetrahydrobiopterin

Aminotransferase

catalyzes the transamination of phenylalanine with pyruvate to form phenylpyruvate

• phenylpyruvate is decarboxylated or reduced

Alkaptonuria

disease caused by a genetic defect in homogentisate dioxygenase

• large amounts of homogentisate are excreted, and its oxidation turns urine black

Amino acids degraded to α-ketoglutarate

• arginine

• glutamate

• glutamine

• histidine

• proline

Amino acids degraded to succinyl-CoA

• isoleucine

• methionine

• threonine

• valine

Branched-chain amino acids degraded in extrahepatic tissues

• isoleucine

• leucine

• valine

Branched-chain α-keto acid dehydrogenase complex

catalyzes oxidative decarboxylation of all three α-keto acids, releasing CO2 and producing the acyl-CoA derivative

Maple syrup urine disease

condition in which the three branched-chain α-keto acids and their precursor amino acids accumulate in the blood and “spill over” into the urine

Amino acids degraded to oxaloacetate

• asparagine

• aspartate

Asparaginase

catalyzed the hydrolysis of asparagine to aspartate

aspartate aminotransferase

catalyzes the transamination of aspartate with α-ketoglutarate to yield glutamate and oxaloacetate