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Amino acid metabolism I
Jana NovotnáDepartment of the Medical Chemistry and Clinical Biochemistry
The 2nd Faculty of Medicine, Charles Univ.
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Metabolic relationship of amino acids
Body proteins
Proteosynthesis Degradation
Amino acidpoolDietary
proteins
Digestion
Transaminatio
n
NONPROTEINDERIVATIVESPorphyrinsPurinesPyrimidinesNeurotransmittersHormonesKomplex lipidsAminosugars
UREA NH3
Carbon skeletonconversion
250 – 300 g/day
acetyl CoASaccharideslipides
CO2
H2O
GlycolysisKrebs cycle
Conversion to
Ketonbodies
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Digestive tractEndopeptidases – hydrolyse the peptide bond inside a chain: pepsin (stomach), trypsin, chymotrypsin, elastase (pancreas)
Exopeptidases – split the peptide bond at the end of a protein molecule:
aminopeptidase, carboxypeptidases, dipeptidases (small intestine)Hydrolysis of proteins polypeptides oligopeptides amino acids intestinal lumen transport to target tissuesPepsin (pH 1.5 – 2.5) – hydrolysis of peptide bond before Tyr, Phe and between Leu and Glu.Trypsin (pH 7.5 – 8.5) – peptide bond after Lys a Arg.Chymotrypsin (pH 7.5 – 8.5) – peptide bond after Trp, Phe,Tyr, Met, Leu.Pancreatic elastase (pH 7.5 – 8.5) - peptide bond after Ala, Gly and Ser
Degradation of amino acids intracellularly the first step is deamination, transamination, oxidative decarboxylation
Enzymes cleaving the peptide bond
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Absorption of amino acids
• Absorption from the lumen of small intestine by transepitelial transport
• Semispecific Na+-dependent transport system
• Na+-dependent carriers transport both Na+ and an amino acid.
• At least six different Na+-dependent carriers:
- neutral AA- proline and hydroxyproline- acidic AA- basic AA (Lys, Arg) and cistine
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Clinical note:
Genetically determined defect in the transport of amino acids across the brush border membranes of cells in both small intestine and renal tubules
Cystinuria – AR disease, caused by mutation in two genes for transporter proteins in the kidney proper reabsorption of basic, or positively charged, amino acids (Lys, Arg and ornithine) and cysteine into bloodstream is prevent Cys is oxidized to insoluble cystine formation of kidney stones renal colic.
Hartnup disease – relatively rare AR disease – defect in tranport of neutral AA including essential (Ile, Leu, Val, Phe, Thr, Trp - availability of essential AA may cause a variety clinical disorders
The urine of newborns is routinely screening.
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g-Glutamyl cycle and amino acid transport
Gamma-glutamyl transferase (gamma-glutamyl transpeptidase, GGT)
Found in many tissues, mainly in the liver.
Diagnostic marker for liver disease - elevations in GGT in patients with chronic viral hepatitis infections.
Transport of AA across cell membrane by reacting with glutathion to for g-glutamyl amino acid
AA is released into the cell. Glutathion is resinthesized.
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Transamination - exchange of NH2 group with C=O
General reactions of amino acid catabolism
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General reactions of amino acid catabolism
Deamination
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General reactions of amino acid catabolism
Decarboxylation
Decyrboxylation of AA gives amines having a variety of functions.
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Transamination reaction
The first step in the catabolism of most amino acids is removal of a-amino groups by enzymes transaminases
or aminotransferases
All aminotransferases have the same prostethic group and the same reaction mechanism.
The prostethic group is pyridoxal phosphate (PPL), the coenzyme form of pyridoxine (vitamin B6)
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Active metabolic form of vitamin B6
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Mechanism of transamination reaction: PLP complex with enzyme accept an amino group to form pyridoxamine phosphate, which can donate its amino group to an a-keto acid.
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All amino acids except threonine, lysine, and proline can be transaminated
Transaminases are differ in their specificity for individual L-amino acid. The enzymes are named for the amino group donor.
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Clinically important transaminases
ALT
Alanine transaminase ALT(previously called serum glutamate-pyruvate transaminase – SGPT)Predominantly found in the liver. Important in the diagnosis of liver (viral hepatitis drug toxicity), ALT is a more specific indicator of liver inflammation than AST.
Aspartate transaminase AST(previously called serum glutamate-oxaloacetate transaminase – SGOT).- Found in the liver, heart, skeletal muscles, kidneys, brain, and red blood cells. - Elevated in liver diseases, myocardial infarction, acute pancreatitis,
acute hemolytic anemia, severe burns, acute renal diseases, musculoskeletal diseases, and trauma (in 1954 defined as a biochemical marker for the diagnosis of acute myocardial infarction)
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Deamination
Amino acids FMN H2O+ +
a-keto acids FMNH2 NH3
L-amino acid oxidase
A. Oxidative deamination
FMN
H2O2 H2O + O2
+ +O2
catalse
B. Nonoxidative deamination
serine
pyruvate
threonine
a-ketobutyrate
+ +
Serin-threonin dehydratase
• L-amino acid oxidase produces
ammonia and a-keto acid directly,
using FMN as cofactor.• The reduced form of flavin must
be regenerated by O2 molecule.
• This reaction produces H2O2
molecule which is decompensated
by catalase.
Is possible only for hydroxy amino acids
NH3 + H2O NH3 + H2O
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Decarboxylation
• process is catalysed by enzymes decarboxylase – cofactor is pyridoxalphosphate
• R-CHNH2-COOH R-CH2NH2 + CO2
• takes place only in small quantities • primary amines
• biologically active amines• hormones (neurotransmitters, coenzymes)
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Biogenic amines
• Tyrosine norepinephrine, epinephrine, dopamine, DOPA
• Histidine histamine• Tryptophane serotonine, melatonine• Ornithine putrescine, polyamines• Glutamate GABA• Serine ethanolamine
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Synthesis of non-essential amino acids
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Overview of the synthesis of non-essential amino acids
The carbon of 10 AA may be produced from glucose through intermediates of glycolysis or the TCA cycle.Tyrosine from phenylalanine.The sulphur of cysteine – from methionine.
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Amino acids derived from intermediates of glycolysis
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The major pathways for serine synthesis from glucose and serine degradation
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Glycine biosynthesis from serine
Reaction involves the transfer of the hydroxymethyl group from serine to the cofactor tetrahydrofolate (THF), producing glycine and N5,N10-methylene-THF.
Copy from: http://themedicalbiochemistrypage.org/amino-acid-metabolism.html
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Glycine oxidation to CO2
Glycine produced from serine or from the diet can also be oxidized by glycine decarboxylase (also referred to as the glycine cleavage complex, GCC) to yield a second equivalent of N5,N10-methylene-tetrahydrofolate as well as ammonia and CO2.
Copy from: http://themedicalbiochemistrypage.org/amino-acid-metabolism.html
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Tetrahydrofolate acts as a carrier of reactive single C units
Copy from: http://www.chembio.uoguelph.ca/educmat/chm452/lectur25.htm
Serine glycine – formation of N5,N10-methylen THFGlycine CO2 - formation of N5,N10-methylen THFHomocysteine methionine – donor of C is N5-methyl THFHistidine degradation – formation of N5-formiminoTHF; N5,N10-metnhenyl a N10-formyl THFTryprophane degradation – formation of N10-formyl THF
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Metabolism of glycine
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Cysteine synthesis
Copy from: http://themedicalbiochemistrypage.org/amino-acid-metabolism.html
1. Conversion of SAM to homocysteine.
2. Condensation of homocysteine with serine to cystathione.
3. Cystathione is cleavaged to cysteine.
Conversion of homocysteine back to Met. N5-methyl-THF is donor of methyl group.
*
*folate + vit B12
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Homocystinuria Genetic defects for both the synthase and the lyase.
Missing or impaired cystathionine synthase leads to homocystinuria.High concentration of homocysteine and methionine in the urine.
Homocysteine is highly reactive molecule.
Disease is often associated with mental retardation, multisystemic disorder of connective tissue, muscle, CNS, and cardiovascular system.
Clinical note
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Relationship between glutamate, glutamine and a-ketoglutarate
a-ketoglutarate glutamate glutamine
NH3
NH3
NH3
NH3
Glutamate + NAD+ + H2O a-ketoglutarate NH3+ + NADH
Glutamate NH3+ glutamine
ATP ADP
Glutamine H2O+ glutamate NH3+
A. Glutamate dehydrogenase
B. Glutamine synthetase (liver)
C. Glutaminase (kidney)
From transamination reactions
To urea cycle
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Amino acid degradation
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Degradation of AA
20 amino acids are converted to 7 products:
pyruvate acetyl-CoA acetoacetate a-ketoglutarate succinyl-CoA oxalacetate fumarate
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Glucogenic amino acids
formed: a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl-CoA
Aspartate Asparagine Arginine Phenylalanine Tyrosine Isoleucine
Methionine Valine Glutamine Glutamate Proline Histidine
Alanine Serine Cysteine Glycine Threonine Tryptophan
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Ketogenic amino acids
formed acetyl CoA or acetoacetate
Lysine
Leucine
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Both glucogenic and ketogenic amino acids
formed: a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl-CoA in
addition to acetyl CoA or acetoacetate
IsoleucineThreonineTryptophanPhenylalanineTyrosine
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Amino acids that form acetyl-CoA and acetoacetate
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Amino acids related through glutamate
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Synthesis and degradation of proline
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Histidine degradation
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Amino acids that form succinyl-CoA
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Amino acids related to oxalacetate
Aspartate and asparagine
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The sulfur for cysteine synthesis comes from the essential amino acid methionine.
SAM serves as a precurosor for numerous methyl transfer reactions (e.g. the conversion of norepinephrine to epinenephrine).
Cysteine and methionine are metabolically related
Condensation of ATP and methionine yield S-adenosylmethionine (SAM)
SAM
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valine isoleucine leucine
a-ketoglutarate glutamate (transamination)
a-ketoisovalerate a-keto-b-methylbutyrate a-ketoisokaproate
oxidative decarboxylationDehydrogenase of a-keto acids*
CO2
NAD+
NADH + H+
isobutyryl CoA a-methylbutyryl CoA isovaleryl CoA
Dehydrogenation etc., similar to fatty acid b-oxidation
propionyl CoA acetyl CoA
acetoacetate
acetyl CoA
propionyl CoA+ +
Degradation of branched amino acids
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Branched-chain aminoaciduriaDisease also called Maple Syrup Urine Disease (MSUD) (because of the characteristic odor of the urine in affected individuals).
Deficiency in an enzyme, branched-chain α-keto acid dehydrogenase leads to an accumulation of three branched-chain amino acids and their corresponding branched-chain α-keto acids which are excreted in the urine.
There is only one dehydrogenase enzyme for all three amino acids.
Mental retardation in these cases is extensive.
Clinical note
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Biosynthesis of tyrosine from phenylalanine
Phenylalanine hydroxylase is a mixed-function oxygenase: one atom of oxygen is incorporated into water and the other into the hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor tetrahydrobiopterin, which is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine reductase
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Tetrahydrobiopterin as a cofactor of hydroxylases
Dihydrobiopterin
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• Hyperphenylalaninemia, phenylketonuria - complete deficiency of phenylalanine hydroxylase (plasma level of Phe raises from normal 0.5 to 2 mg/dL to more than 20 mg/dL).
• The mental retardation is caused by the accumulation of phenylalanine, which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of α-ketoglutarate.
• Absence of α-ketoglutarate in the brain shuts down the TCA cycle and the associated production of aerobic energy, which is essential to normal brain development.
• Newborns are routinelly tested for blood concentration of Phe.
• The diet with low-phenylalanine diet.
Clinical note
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Tryptophan catabolism
Tryptophan has complexcatabolic pathway: 1. the indol ring is
ketogenic2. the side chain alanin
gluconeogenesis
Xanthurenic acid isexcrete in the urine.Nicotinamide NAD andNADP.
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Enzymes which metabolised amino acides containe vitamines as cofactors
THIAMINE B1 (thiamine diphosphate) oxidative decarboxylation of a-ketoacids
RIBOFLAVIN B2 (flavin mononucleotide FMN, flavin adenine dinucleotide FAD)oxidses of a-amino acids
NIACIN B3 – nicotinic acid (nikotinamide adenine dinucleotide NAD+
nikotinamide adenine dinukleotide phosphate NADP+)dehydrogenases, reductase
PYRIDOXIN B6 (pyridoxalphosphate)transamination reaction and decarboxylation
FOLIC ACID (tetrahydropholate)Meny enzymes of amino acid metabolism
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Pictures were taken from textbooks:
Marks´ Basic Medical Biochemistry A Clinical Approach. Four edition M. Lieberman, A.D. Marks ed., 2013. Essentials of Medical Biochemistry With Clinical Cases. First edition. N.V. Bhagavan, Chung-Eun Ha ed., 2011.