AMINO ACIDS CATABOLISM

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Amino acid degaradation

The nitrogenous compound degradation in mammals generally follows a particular mechanism. 1. the nitrogen in amino acids is removed by deamination reaction and converted to ammonia-which is toxic, therefore need to be detoxified and excreted as soon as possible. Ammonotelic organism (e.g fish) excreted ammonia directly into surrounding in the form of dissolved ammonia. Mammals generally have to conserve water, therefore cannot excrete as dissolved ammonia- but convert it to urea a.k.a ureotelic organism. Uricotelic organism (bird, certain reptiles and insect) have more stringent water conservation problem, therefore convert ammonia to uric acid. In human and birds- uric acid is also the nitrogenous product of purine metabolism.
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Amino acids catabolism usually begins by the removal of the amino group through:-Transamination - oxidative deamination
Amino group is then dispose as urea. Carbon skeleton produced from standard amino acids are then degraded to form seven metabolic product :- acetyl-CoA - acetoacetyl-CoA - pyruvate - a-ketoglutarate - succinyl CoA - fumarate - oxaloacetate
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Those amino acids that can be converted to acetyl-CoA and acetoacetyl-CoA are referred to as KETOGENIC because they can be converted to either fatty acids or ketone bodies.

Those aa than can be degraded to pyruvate, a-ketoglutarate, succinyl-CoA , fumarate and oxaloacetate, are referred to as GLUCOGENIC they can be used in gluconeogenesis. All amino acids except lysine and leucine are at least partly glucogenic. Lys and leu are purely ketogenic. Amino acid that yield acetyl-CoA can be divided into 2 groups:i) Those that yield pyruvate as intermediate ii) Those not involves pyruvate as intermediate Group (i) includes Ala, Cys, Gly, Ser, and Thr. (ACGST) Group (ii) includes Phe, Lys, Leu, Trp, and Tyr. (FKLWY)
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In muscle, excess amino groups are transferred to a-ketoglutarate to form glutamate.

In muscle cell NH3 NH3 a-ketoglutarate + amino acid glutamate + a-keto acid. Amino group in glutamate is transported to liver by the alanine cycle. In blood NH3 NH3 Glutamate + pyruvate alanine + a-ketoglutarate. In the liver, glutamate is formed as the rxn catalysed by alanine transaminase is reversed followed by oxidative deamination of glutamate to produce a-ketoglutarate and free +NH4 i) Alanine + a-ketoglutarate glutamate + pyruvate ii) Glutamate + NAD+ + H2O a-ketoglutarate + NADH + H+ + +NH4
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NH3

NH3

NH3

UREA CYCLE
In the matrix of mitochondria of hepatocytes 1. HCO3- + +NH4
carbamoyl phosphate synthase

2ATP

2ADP + Pi + 3H+

O O II II NH2-C O - P OI Ocarbamoyl phosphate

Bicarbonate react with ammonium ion to form carbamoyl O phosphate. 2ATP are used- one to activate the II NH C bicarbonate, another to phosphorylate the carbamate, 2 - H The reaction is irreversible.

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O
II

O
II I

NH2 C O -P OO-

Ornithine transcarbamyolase

H O I II + H3N C C OI CH2 I CH2 I CH2 ornithine I + NH3

Pi

H O I II + H3N C C OI CH2 I CH2 I CH2 citrulline I N H I C O I NH2

Carbamoyl phosphate react with ornithine to form citrulline. Citrulline is then transported to the cytoplasm.
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In the cytosol
H O I II + H3N C C I CH2 I CH2 I CH citrulline I 2 N H I C O I NH2 H O I II + H3N C C OO I CH2 ATP I CH 2 H O AMP + PPi I I II COO CH H3N+ C C OI I 2 I N H CH2 CH2 I I + I C NH - CH C=O I I INH 2 COOO aspartate argininosuccinate synthase argininosuccinate

Citrulline react with aspartate to form argininosuccinate

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H O argininosuccinate lyase I II + H3N C C O I CH2 I COOCH2 I I COO CH CH2 I I II N H CH2 CH I I I C NH - CH COOI I NH2 fumarate COOargininosuccinate

H O I II + H3N C C OI CH2 I CH2 I CH2 Arginine I N H I C +NH2 I NH2

Argininosuccinate lyase cleaves argininosuccinate to release arginine and fumarate

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H O I II + H3N C C OI CH2 I H2O CH2 I CH2 Arginine I N H I C +NH2 I NH2

arginase

NH2 O= C NH2 urea

H O I II + H3N C C OI CH2 I CH2 I CH2 ornithine I + NH3

Arginase catalysed the hydrolysis of arginine to form ornithine and urea. Note: Three ATPs is consumed in the synthesis of one molecule of urea.
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citrate amino acid oxaloacetate

malate

a-keto acid

Aspartate-arginino succinate cycle aspartate argininosuccinate fumarate

Aspartate argininosuccinate cycle temporarily shut down the citric acid cycle to allow the conversion of oxaloacetate to aspartate

Urea cycle citrulline arginine

ornithine Carbamoyl phosphate urea

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(Primary pathway) Thr. dehydrogenase

a-amino-b-ketobutyrate
CoASH a-amino-b-ketobutyrate lyase Acetyl CoA

Threonine

NADH + H+

NAD+
N5, N10 methylene THF

H2O
+

glycine

cysteine
THF CoASH

a-amino-b-ketobutyrate
NAD+

NH4

cysteine sulfate
transamination desulfuration NAD+

serine
Ser. dehydratase
+

NH4 CoASH CO2 NADH + H+

pyruvate
CO2

Alanine

Glu-ala transaminase NADH + H+

Acetyl-CoA

Propionyl-CoA (Pathway in primate)

AMINO ACIDS FORMING ACETYL-CoA

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The catabolic pathway of Thr, Gly, Ser, Ala, and Cys to acetyl-CoA with pyruvate as intermediate

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Tryptophan

NH3-CH-COOI CH2 I

Phenylalanine

Tyrosine
alanine

Leucine

Lysine
formate
+

fumarate

NH3-CH-COOI CH2 I CH2 I CH2 I CH2 I + NH3

a-ketoadipate

Acetoacetate

Acetoacetyl-CoA

Acetyl-CoA

AMINO ACIDS FORMING ACETYL-CoA

Catabolic pathway of Trp, Phe, Tyr, Leu, and Lys to acetyl-CoA (pyruvate is not an intermediate)
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The conversion of Phe to Tyr

Catalysed by phenylalanine-4-monooxygenase and irreversible.

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AMINO ACIDS FORMING a-KETOGLUTARATE Proline Arginine

Glutamate-g-semialdehyde

Histidine

Glutamate

glutamine

a-ketoglutarate

Catabolic pathway of Arg, Pro, His, Gln, and Glu to a-ketoglutarate

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AMINO ACIDS FORMING SUCCINYL-CoA Methionine Isoleucine Valine

Propionyl-CoA

Methylmalonyl-CoA

Succinyl-CoA

Catabolic pathway of Met, Ile, and Val to succinyl-CoA

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AMINO ACIDS FORMING OXALAOACETATE

Asparagine

Aspartate

Oxalaoacetate

Catabolic pathway of Asparagine and Aspartate to oxaloacetate

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Tyr acetoacetate

Phe Cys

Leu Ser Pyruvate Gly

Ala
Thr

Trp

Acetoacetyl-CoA a-ketoadipate Trp Lys Asp oxaloacetate malate Asn fumarate citrate Acetyl-CoA

Arg

Pro

Krebs cycle

isocitrate CO2 a-ketoglutarate CO2

Glutamate -g-semialdehyde

glu

succinate To acetyl CoA Met

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succinyl-CoA Propionyl CoA Ile

gln Methymalonyl semialdehyde

His

Val 22

Degradation of selected neurotransmitters

To maintain precise information transfer, neurotransmitter must be quickly degraded or removed from the synaptic cleft. Acetylcholine (muscle contraction initiator) action is terminated by the enzyme acetylcholinesterase. (acetylcholine must be destroyed rapidly so that muscle can relax before the next contraction). Acetylcholineesterase is a serine esterase that hydrolyses acetycholine to acetate and choline. This enzyme is irreversibly inhibited by DFP (diisoprophylfluorophospahate), which caused muscle paralysis. With each nerve impulse , more acetylcholine molecules enter the neuromuscular synaptic cleft, accumulates and overstimulating the muscle and led to paralysis. Affected individuals suffocate because of paralysed respiratory muscle. 9/4/2013 23

Degradation of selected neurotransmitters

Catecholamines epinephrine, norepinephrine and dopamine are inactivated by oxidation reactions catalysed by monoamine oxidase (MAO). The catecholamine have to be transported out of the synaptic cleft before inactivation because the MAO is found within the nerve endings. Epinephrine, released as a hormone from the adrenal gland, is carried in the blood and is catabolised in nonneural tissue (perhaps the kidney). Catecholamine also inactivated in methylation reactions catalsed by catechol-O-metyltransferase (COMT). Serotonin is degraded in two step pathway. First serotonin is oxidised by MAO. The product, 5hydroxyindole-3-acetaldehyde, is then further oxidised by aldehyde dehydrogenase to form 5-hydroxyindole-3acetate.
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Clinical manifestation/disease related to amino acid metabolism disorder

1. PKU (phenylketourea) accumulation of Phe in nervous tissue. Phenyl keto acid in urine. Caused mental retardation.

2. Tyrosinemia accumulation of tyrosine in the blood. Also cause mental retardation.

3. Alkaptourea def. of homogentisate oxidase in the metabolism of tyrosine. Urine turn black due large quantities of homogentisic acid. Disorder will lead skin getting darker in later years and high susceptible to athritis. 4. Albinism genetic defect of the tyrosinase enzyme. Skin, eye, hair contain no alittle pigment (melanin) 5. Hyperhomocytienemia accumulation of homocysteine and methionine. Suggested to induced atherosclerosis and 9/4/2013 thrombosis.

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