nitrogen metabolism pratt and cornely chapter 18
TRANSCRIPT
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Nitrogen Metabolism
Pratt and Cornely Chapter 18
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Overview
• Nitrogen assimilation• Amino acid biosynthesis– Nonessential aa– Essential aa
• Nucleotide biosynthesis • Amino Acid Catabolism• Urea Cycle
Juicy Steak Part 2
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Nitrogen fixation
• Bacteria• Nitrogenase• Costly—16 ATP
per N2 molecule
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Assimilation into Amino Acids• In microorganisms/plants: assimilation of
ammonia is key—synthesis of most amino acids– Glutamine synthetase incorporates amino group– Coupled to glutamine synthase: reductive
amination of a-ketoglutarate to glutamate– Glutamate distributes amino to new amino acids
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Assimilation into Amino Acids• In humans: acquire nitrogen in amino acids– No need for glutamine synthase– Glutamate distributes amino to new amino acids
through transamination– Glutamine synthetase used to “mop up” ammonia
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Transamination
• Transfers assimilated nitrogen into all other amino acids
• Requires PLP cofactor
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Biosynthesis
• Dietary consideration
• Ambiguous– Stage of life (Arg)– Precursor (Tyr, Cys)
• Mechanism of biosynthesis can be grouped
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Amino Acid Biosynthesis
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Non-essential Amino Acid Biosynthesis• Transamination– Pyruvatealanine– Oxaloacetateaspartate– a-ketoglutarateglutamate
• Amidation– Glutamine (glutamine synthetase)– Asparagine (asparagine synthetase)
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Glutamate Backbone
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Serine/Glycine
• 3-phosphoglycerate Serine• Serineglycine– THF as a major one-carbon transfer vitamin
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Cysteine and Tyrosine
• Serinecysteine by incorporating sulfur from homocysteine (Made from methionine)
• Oxidation of Phe gives tyrosine
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Neurotransmitters
• Which amino acid?
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Amino acid catabolism
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Ketogenic vs. Glucogenic
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Problem 35
• The catabolic pathways for the 20 amino acids ary considerably, but all amino acids are degraded to one of seven metabolites: pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate, acetyl CoA, are acetoacetate. What is the fate of each of these metabolites?
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Amino Acid Degradation
• Transamination and deamination• Then carbon chain is metabolized• Examples:
-O
NH2
O
-O
O
O
Acetyl CoA
Alanine Pyruvate
Glucose
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Pyruvate Producing
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Glutamate Family
• 25% of dietary intake
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Thr: Glucogenic and Ketogenic
• Gly—major source of methylene-THF
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Branched Amino Acids
• Major energy source in muscle• Steps of degradation– Transamination– Oxidative decarboxylation (Pyruvate DH)– Beta oxidation
• Valine: succinyl CoA• Isoleucine: succinyl CoA and acetylCoA• Leucine: acetyl CoA and ketone body
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Problem 40
• Leucine is degraded to acetyl CoA and acetoacetate by a pathway whose first two seps are identical to those of valine degradation (Figure 18-11). The third step is the same as the first step of fatty acid oxidation. The fourth step involves an ATP-dependent carboxylation, the fifth step is a hydration, and the last step is a cleavage reaction to give products. Draw the intermediates of leucine degradation.
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Aromatic Amino Acids
• Complicated• First recognition of inborn errors of
metabolism
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Problem51
• List all the reactions in this chapter that generate free ammonia.
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Ammonia Processing• Most tissues: glutamine synthetase “mops up”– glutamine sent through blood to liver– Deaminated in liver to give glutamic acid• glutaminase
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Ammonia Processing• Muscle: The alanine-glucose cycle• Glutamate also accepts amino group from
other amino acids
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Glutamate Dehydrogenase
• Reversible reaction• Grabs free ammonia and releases it in liver
mitochondria
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Role of Liver Mitochondia
• Sequester toxic ammonia• Make less toxic, execrable form• Urea Cycle
O
NH2H2N
bicarbonate
ammonia(from glutamate)
aspartate(can be derived from glutamate via transmination)
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Carbamoyl phosphate
• Cost of 2 ATP– Phosphate leaving group
• Activation of ammonia for– Excretion– biosynthesis
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Problem 52
• Which three mammalian enzymes can potentially “mop up” excess NH4
+?
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Urea Cycle
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Chemistry of Urea Cycle
• Catalytic ornithine
• Fumarate • Urea = 4 ATP
NH2
H3N
O
O
+ ATP
+ AMP
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Compartmentalization
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Urea Cycle Regulation• Carbamoyl phosphate synthetase• Amino acid catabolism boosts acetyl CoA and
glutamate levels• Produces activator
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Problem 55
• An inborn error of metabolism results in the deficiency of arginosuccinase. What could be added to the diet to boost urea production aid in ammonia secretion? (Argininosuccinate can be excreted.)
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Solving Metabolic Problems
• Arginosuccinase deficiency• Low protein diet– Minimize ammonium
• High arginine diet– Provide carrier
X
excreted
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Nitrogen Flow Overview
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Summary: Main Players
• Glutamate: in liver, receives nitrogen from AA, then ammonia is released in liver mitochondria
• Glutamine: ammonia transport; biosynthesis• Alanine: ammonia transport• Aspartate: nitrogen donor to urea• Arginine: urea cycle