Amino acid metabolism II - medchem.upol.cz metabolismII.pdf · Amino acid metabolism II . Fates of amino acid carbon skeleton – degradation to common intermediates – pyruvate,

Amino acid metabolism II

Fates of amino acid carbon skeleton –degradation to common intermediates– pyruvate, intermediates of citric acid cycle,

acetyl-CoA

Glucogenic AA– precursors of glucose

- degradation to pyruvate or citricacid cycle intermediates–can beconverted to oxaloacetate – keeintermediate of gluconeogenesis

- most AA

Ketogenic AA

– precursors of ketone bodies

- degradation to acetoacetate (a ketonebody) or to acetyl-CoA(a substrateof ketogenesis)

- Lys, Leu , Ile, Phe, Tyr, Trp

bothgluco- and ketogenic AA

Conversion of amino acids to glucose (examples)

Alanine Pyruvate Phenylalanine, Tyrosine

Aspartate Oxaloacetate Malate Fumarate

Succinate

Phosphoenolpyruvate Succinyl-CoA

2-Phosphoglycerate α-Ketoglutarate

3-Phosphoglycerate

1,3-Bisphosphoglycerate Glutamate

glyceraldehyde 3-phosphate Dihydroxycetone phosphate

Fructose 1,6-bisphosphate

Fructose 6-phosphate

Glucose 6-phosphate

Glucose

α-keto-glutarate

glutamate

AST

ALT

α-keto acid

amino acid

Metabolism of individual aminoacids

Each AA– specific pathway of degradation

to common intermediates(pyruvate, citric acid cycleintermediates, acetyl-CoA)

- specific transformation to specialized nitrogenoussubstances(catecholamines, nucleotides , porphyrins, creatine…)

- numerous enzyme defects in AA metabolism – genetic diseases

~ 120 genetic disorsders of AA transport and metabolism

~ 25 disorders associated withmental retardation

Tetrahydrofolate (THF) – important cofactor in AA meta bolism

- derived from vitamin - folic acid

- the cofactor function – mobilization, interconversion and utilization ofsingle-carbon functional groups= one-carbon units

methylmethylene( hydroxymethyl)formylformimino

sources: serine, glycine, histidine

-one-carbon unitsattached to N5and/or N10 ofthe THF molecule

- THF-one-carbon unit - involved in biosynthesisof purine nucleotides, pyrimidine nucleotides(donor of thymine methyl group), methioninesynthesisfrom homocysteine

histidine

S-Adenosylmethionine (SAM) –methyl group donor

- Methyl group transferred to an acceptor (dopamine, noradrenaline, ethanolamine…)- Resulting S-adenosylhomocysteine hydrolyzed to homocysteine- Folate/THF deficiency hyperhomocysteinemia - risk factor of cardiovascular diseases

Metabolism of aromatic amino acids

Proteins Proteins Thyroxine

Phenylalanine Tyrosine CO2 + H2O + urea

melanocytes adrenal medula, CNS

Melanin Catecholamines

Metabolic defects (enzyme deficiences) genetic diseases:

1 - Hyperphenylalaninemia - phenylketonuria1 : 10 000 (world)1 : 5 – 8 000 (CR)

2 – Tyrosinemia (I, II, III )3 - Alcaptonuria4 - Albinism

liver

1 2, 3

4

Degradation of phenylalanine and tyrosine

citric acid cycle - ATPglucose

ketone body

acetyl-CoA

Phe, Tyr – both glucogenic and ketogenic AA

Phenylketonuria (PKU)

Urine1-2 g/day

- Deficiency ofphenylalanine hydroxylase, tetrahydro-biopterin (THBP) or dihydropteridine reductase

- Accumulation of phenylalamine in blood and tissues- Alternative metabolism – transamination of Phe and

transformations of resulting phenylpyruvate

- Mental retardation

- Treatment:phenylalanine hydroxylase deficiency – diet low in

phenylalanine, high in tyrosine throughoutfirst decade or for life

THBP or dihydropteridine reductase deficiency –phenylalanine-low diet, supplying THBP andDopa, 5-OH-tryptophane – precursors of neuro-transmitters

detection inurine with FeCl3

Alcaptonuria – deficiency ofhomogentisate oxygenase –homogentisic acid eliminated in urine – darkening of urine owing tooxidation of homogentisate – „dark urine disease“

Tyrosinemias –increased level of tyrosine in blood, tyrosinuria;inflamations (from intracellular crystalization of tyrosine), mentalRetardation

Albinism - lack of melanin (brown pigment of skin, hair , eyes)production – deficiency oftyrosinase

Tyrosine Dihydroxyphenylalanine Dopa quinone Melanintyrosinase tyrosinase

Catecholamines

= dopamine, norepinephrine , epinephrine(noradrenalin) (adrenalin)

neurotransmitters hormonesynthetized in:brain, adrenal medulla adrenal medulla

Structural basis:catechol pyrocatechol = o-dihydroxybenzen

Synthesis: from tyrosinevia dihydroxyphenylalanine (= Dopa) hydroxylation, decarboxylation – essential reactions

Essential role of tetrahydrobiopterine in hydroxylation reactions

Disorders in catecholamine biosynthesis

Parkinson´s disease– deficiency ofdopaminesynthesis – affect nerve transmission

in the substancia nigra of the upper brain stem involuntary tremor, decreased

motor power and control, postural instability, muscular rigidity

Treatment: ! dopamine cannot cross blood-brain barier- thus administration of itsprecursor = Dopa (crosses blood-brain barier) together withDopa-decarboxylaseinhibitors

prevent decarboxylation of Dopa to dopamine in liver

Increased dopamineproduction – associated withschizophrenia, drug abuse

Pheocytochroma –tumor of the adrenal medulla – overproduction of norepinephrine, epinephrine permanet hypertension, hyperglycemia, glucosuria

Inactivation of catecholamines

1. MAO – monoamine oxidase (flavoprotein – FAD)2. COMT - catechol-O-methyltransferase (S-adenosylmethionine = SAM)

FAD FADH2 H2OO

1. R – CH2 – NH2 R – CH = NH R – C + NH3H

Amine Aldehyde

2.

S-adenosyl-methionine

CH3

MAO, COMT, oxidation

VANILYLMANDELIC ACID

CH3

COOH

detection in urine, markerof catecholamine overproduction–nuroblastoma, pheochromocytoma

• Rapid inactivation – half–life ~ 20 seconds• Enzymes for inactivation present in most tissues, particularly in liver

homocysteine

Biosynthesis of other neurotransmitters

Decarboxylation of AA –essential reaction

Hydroxylation in serotoninsynthesis – THBP-dependent

Biosynthesis of amino acids– transamination ofα-keto acids (= metabolic intermediates)

10 amino acids (noneseential)

Precursors: αααα-ketoglutarate glutamate

pyruvate alanine

oxaloacetate aspartate asparagine

3-phosphoglycerate serine

glutamineprolinearginine

(cysteine)

glycine

transaminace

transamination

transamination

intermediate of glycolysis

NAD+ NADH + H+

transaminationH2O P

H2N H H2N H

H

serine

1. Essentiala) Totally essential Lys, Thr Human can synthesize neither carbon chain,

nor introduce –NH2 group

b) With essential Ile, Leu, Val, Human cannot synthesize carbon chain,carbon chain Met, Phe, however can synthesize these AA from

Trp, His the supplied oxo acids

2. Conditionally essential Tyr, Cys, Synthesized in the organism from non-Tau, Orn essential AA: Phe→ Tyr,

Met → Cys→ Tau, Arg → Orn

3. Essential Cys, Tyr Long-term parenteral nutrition,in overloaded organism Arg, Orn elevated protein catabolism

Cit, Tau

4. Nonessential Ala, Asp, Synthetized de novo in humansAsn, Glu, Gln, Gly, Pro, Ser

EsEsssenentialtial aminoamino acidsacidsrequired to be supplied by the diet – precursors of the synthesis (keto acids) doesnot exist: histidine, tryptophane, phenylalanine, leucine, isoleucine, valine, lysine, threonine, methionine

Methylmalonate acidemia/aciduria

• disorder of metabolism of aminoacids degraded to propionyl-CoA(Ile, Val, Thr Met)

• genetic defectof methylmalonyl-CoA-mutase = the enzyme essential for conversion of propionyl-CoA to succinyl-CoA,:or deficiency of vitamin B12 = cofactor of the enzyme

• elevated level of methylmalonatein the blood, excretion ofmethylmalonate into the urine

• metabolic acidosis, developmentalproblems, death

Amino acids converted to propionyl-CoA succinyl-CoA

Degradation of isoleucine– example of branched-chain amino acids breakdown

transamination

oxidativedecarboxylation

β-oxidation

β-oxidation