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Pratt and Cornely Chapter 18
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 glutamate synthase: reductive amination of a-ketoglutarate to glutamate
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Net Reaction a-KG + NH3 +ATP + NADPH Glu + ADP + NADP+
Ultimately, this is incorporation of ammonia into an amino acid Glutamate can then be used to distribute nitrogen into other amino acids (transamination)
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Assimilation into Amino Acids
In humans: acquire nitrogen in amino acids Amino acids in diet Glutamate distributes amino group to new amino acids through transamination No need for glutamate synthase Glutamine synthetase used for different purpose: 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 Serinecysteine by incorporating sulfur from homocysteine (Made from methionine)
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Phenylalanine Monooxygenase uses O2 for hydroxylation
Other atom ends up in water Requires a reducing cofactor called tetrahydrobiopterin Also first step in catabolism of phenylalanine PKU
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Neurotransmitters Which amino acid?
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Nucleotide Biosynthesis
5-PRPP Purine: base built onto ribose Asp, Gly, Glu, THF, bicarbonate IMP produced
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AMP/GMP Production Branched pathway AMP: amination GMP: oxidation
Branch allows for reciprocal regulation
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Pyrimidines Contrast Base made first, then attached to 5PRPP
Not branched: UMP made to UTP then to CTP
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Ribonucleotide Reductase
Essential reaction: reduction to make dNDP Very difficult reaction Free radical Enzyme is oxidized in the process Reduced by thioredoxin In turn, thioredoxin reduced by NADPH
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Production of TMP dUTP must be converted to TMP quickly
Methylene donated from THF by thymidylate synthase THF oxidized to DHF Chemotherapy: dUMP analog
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Regenerating THF DHF must be reduced to THF by DHF reductase
NADPH dependent Chemotherapy target DHF analogs such as methotrexate
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Catabolism Salvage pathway through phosphorolysis
Purines made into uric acid (waste) Pyrimidines broken down into catabolic intermediates
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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 vary considerably, but all amino acids are degraded to one of seven metabolites: pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate, acetyl CoA, or 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:
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Pyruvate Producing A variety of enzymes convert 3-C chains
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Glutamate Family 25% of dietary intake
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Thr: Both Glucogenic and Ketogenic
Many mammals: or aminoacetone pyruvate In humans:
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Glycine Cleavage system
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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 steps 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 Monoxygenases and Dioxygenases
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” ammonium generated in metabolism glutamine then 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
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Carbamoyl phosphate Cost of 2 ATP Activation of ammonia for
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 + 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 argininosuccinase. 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 excreted X
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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
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