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Degradation of amino acids. Amino acid breakdown can yield: Acetyl-CoA a -KG Succinyl-CoA OAA fumarate. a -KG is generated from five amino acids. Proline Glutamate Glutamine Arginine Histidine. Not a surprise.
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Degradation of amino acids • Amino acid breakdown can yield: • Acetyl-CoA • a-KG • Succinyl-CoA • OAA • fumarate
a-KG is generated from five amino acids • Proline • Glutamate • Glutamine • Arginine • Histidine
Not a surprise • Proline, glutamate, arginine, and glutamate are synthesized from a-KG, here use distinct enzymes for breakdown • But, histidine is not; A completely different pathway for histidine catabolism than for anabolism, • In this case, incoming amino acid (glutamate) binds, donates its amino group to pyridoxal phosphate, and leaves as an a-keto acid (a-KG). Then, an incoming a-deto acid binds and accepts the amino group and leaves as an amino acid
Four amino acids are converted to Succinyl-CoA • Methionine • Converted to homocysteine through methyl group transfer, generates cysteine as converted to a-ketobutyrate • Isoleucine • Transamination, oxidative decarboxylation to acetyl-CoA and propionyl CoA • Valine • Transamination, decarboxylation to propionyl CoA • Threonine • a-ketobutyrate generated and converted to propionyl CoA
Propionyl-CoA is a common intermediate for amino acids succinyl-CoA
Branched-chain a-keto acid dehydrogenase complex • In certain body tissues, this enzyme catalyzes the oxidative decarboxylation of valine, isoleucine, and leucine yielding CO2, and acyl-CoA derivatives. • Shares ancestry with pyruvate dehydrogenase complex, a-KG dehydrogenase complex – another example of gene duplication
Fate of metabolites derived from amino acids • In addition to feeding the citric acid cycle, amino acids can result in ketone bodies, while others are gluconeogenic
Ketone bodies • The six amino acids that are degraded to acetoacetyl-CoA and/or acetyl-CoA (in blue on previous slide) can be converted to acetoacetate and b-hydroxybutyrate
Gluconeogenic amino acids • Amino acids that are degraded to pyruvate, a-KG, succinyl-CoA fumarate, and/or OAA can be converted to glucose
Tempting to take a dietary perspective on carbohydrate and protein metabolism, but…
You seen this many, many times • All aminotransferases have PLP
PLP enzymes • Generally found in enzyme active site covalently bound to amino group of lysine
Aminotransferases exhibit Ping-Pong kinetics • Ping-pong – no ternary complex is formed between substrates and enzyme; first substrate binds, reacts, then that products leaves before second substrate binds
Ammonia from amino acid catabolism • During amino acid breakdown, amino is generally transferred to glutamate (serves as nitrogen source and sink) • From there, amino group can be released as ammonia
Transdeamination • The combined action of aminotransferase and glutamate dehydrogenase is called transdeamination • Glutamate dehydrogenase operates at an important intersection of carbon and nitrogen metabolism – as a result, highly regulated
Linkage of TCA with aa catabolism by allostery • ADP is a positive effector of glutamate dehydrogenase, while GTP is a inhibitor
Ammonia is toxic, so cells need to get rid of it… • Fix ammonia onto glutamate to form glutamine and use as a transport mechanism • Transport ammonia by glucose-alanine cycle • Excrete nitrogenous waste through urea cycle
Ammonia transport using alanine • Alanine aminotransferase transfers the a-amino group from glutamate to pyruvate, forming alanine • This shuttle funnels ammonia out of tissues that have high glycolytic flux, to the liver, which can remove ammonia via urea cycle
Dumping ammonia as urea • The glutamine, glutamate, and alanine feed the urea cycle • The urea cycle generates urea, which can be deposited as waste • The urea cycle spans both the cytosol and mitochondria and four intermediates – you are responsible for the urea cycle
Entering the cycle • Ammonia derived from glutamate or glutamine is immediately linked to bicarbonate – catalyzed by carbamoyl phosphate synthetase I (mitochondrial)
Starting the cycle • Carbamoyl phosphate reacts with ornithine to form citrulline with relase of inorganic phosphate (similar to OAA and acetyl-CoA) – catalyzed by ornithine transcarbamoylase • Citrulline is passed to cytosol, where a second amino group is introduced via aspartate to form argininosuccinate – catalyzed by argininosuccinate synthetase with an ATP requirement
Producing urea • Argininosuccinate lyase generates fumarate and arginine from argininosuccinate • Cytosolic enzyme arginase cleaves arginine to yield urea and ornithine • Ornithine is transported back to the mitochondria to start another round of the urea cycle • Substrate channeling!! – except urea
Urea cycle and citric acid cycle can be linked • Fumarate generated by the urea cycle can be converted to OAA in cytosol, and transported to mitochondria for use in citric acid cycle • Conversely, transamination of OAA in mitochondria yields aspartate, which is used in the cytosolic urea cycle
Urea cycle regulation • More protein metabolism, more urea production • Carbamoyl phosphate synthetase I is allosterically activated by N-acetyl- glutamate
The urea cycle is cost effective • Looking at the urea cycle you observe three ATP spent for every turn, BUT generation of OAA from fumarate yields an NADH which can be used to generate 2.5 to 3 ATP via oxidative phosphorylation