-ketoglutarát

szukcinil-KoA

fumarát

oxálacetát

citrát CC

L-glutamát

Arg, His, Gln, Pro

Ala, Cys, Gly, Hyp, Ser, Thr

Piruvát

Acetil-KoA

Ile, Leu,Trp

Leu, Lys, Phe, Trp, Tyr

Acetoacetil-KoA

L-Asp, L-Asn

Ile, Met, Val

Tyr, Phe

Phe – Tyr conversionHyperphenylalaninaemy I:

henylalanin-hydroxylase (PKU classic)

Dihydrobiopterin-reductase (hyperphenylalanaemy II, III)

Dihydrobiopterin biosynthesis damage (hyperphenylalaninaemy IV, V)

Phe – Tyr conversionHyperphenylalaninaemy I:

phenylalanin-hydroxylase (PKU classic)

Dihydrobiopterin-reductase (hyperphenylalanaemy II, III)

Dihydrobiopterin biosynthesis damage (hyperphenylalaninaemy IV, V)

Alternative degradation products of Phe

CH2 CH COOH

NH2

-ketoglutarát

Glu

CH2 CH COOH

O

Phe

Fenilpiruvát

NADH2NAD+

CH2 CH COO-

OH

Fenillaktát

CH2 COO-

H2O

CO2

NAD+

NADH2

Fenilacetát

CH2 C

O

N C

CONH2

CH2

CH2

COO-

H

FenilglutaminGln

H2O

Plasma (mg/dL) Plasma (mg/dL) Urine (mg/dL) Urine (mg/dL)

Metabolite Normal Phenylketonuric Normal Phenylketonuric

Phenylalanine 1—2 15—63 30 300—1000

Phenylpyruvate 03—1.8 300—2000

Phenyllactate 290—550

Phenylacetate Increased

Phenylacetylglutamine 200-300 2400

Analysis of blood and urine samples of PKU patients

-ketoglutarát

szukcinil-KoA

fumarát

oxálacetát

citrát CC

L-glutamát

Arg, His, Gln, Pro

Ala, Cys, Gly, Hyp, Ser, Thr

Piruvát

Acetil-KoA

Ile, Leu,Trp

Leu, Lys, Phe, Trp, Tyr

Acetoacetil-KoA

L-Asp, L-Asn

Ile, Met, Val

Tyr, Phe

Catabolism of tyrosine

Catabolism of tyrosine

6

7

4

5

OH

CH23

CH2 COO-

1

NH3

+

8

9

4

OH

CH2

CCOO-1

OL-Glu

[O] CO21

OH

CH2COO-

OH-KG

L-Tyr p-hidroxifenil-piruvát Homogentizát

Tirozintranszamináz

p-hidroxifenil-piruvát-hidroxiláz

C

CH2

C

O

O-O

O

C

OO-

CH2

O

C

OO-

C

O

CH2

C

O

O-8

92

3 -OOCHC5

6CH

CO

CH2

CO

O-

7

8

9

Maleiloacetoacetat Maleiloacetoacetat

Maleiloacetoacetatcisz, transz izomeráz

HO

Fumariloacetoacetát

-OOCCH

HCCOO-

CH3

C

CH2

COO-

O

Acetil-CoA + Acetát

Acetoacetát

Fumarát

-ketotiolázfumarilo-acetoacetáthidroláz

H2O

Tyr & metabolic disorders

Tyrosinemia type I: Enzyme def.: fumaryloacetoacetate & maleilo-

acetoacetate hydrolase [Tyr]plasma 6-12 mg/dl, [Met] elevated

Acut tyrosinosis: „cabbage odor”, diarrhea, vomiting, death at age 6-8 month

Chronic tyrosinosis : enyhébb tünetek, halál ~10 éves korban

Tyr & metabolic disorders

Tyrosinemia type II: Tyrozine transaminase[Tyr]plasma 4-5 mg/dlLesion of eyes and skinMental retardation

Neonatal tyrosinemia:Relative deficiency of p-hydroxy-phenylpyruvate-

hydroxylase Food low in proteins

Tyr & metabolic disorders

Alcaptonuria (described by Garrod in 1859)

Defect of homogentisate 1,2 digoxigenase

Urine – dark colourOochronosis

O

O

CC

O-

O

Benzokinon acetát

-ketoglutarát

szukcinil-KoA

fumarát

oxálacetát

citrát CC

L-glutamát

Arg, His, Gln, Pro

Ala, Cys, Gly, Hyp, Ser, Thr

Piruvát

Acetil-KoA

Ile, Leu,Trp

Leu, Lys, Phe, Trp, Tyr

Acetoacetil-KoA

L-Asp, L-Asn

Ile, Met, Val

Tyr, Phe

Tryptophane(1) tryptophan oxygenase, (2) kynurenine

formamidase, (3) kynurenine hydroxylase, (4) kynureninase, (5) aminotransferase, (6) 3-hydroxyanthranilate

oxidase, (7) spontaneous

nonenzymatic reaction, (8) picolinate carboxylase, (9) quinolinate

phosphoribosyltransferase,

(10) aldehyde dehydrogenase, and

(11) complex series of reactions

L-Trp - catabolism

N

CH2

CH

NH3+

COO-

H HN

CH2

CH

NH3+

COO-

O

CHO

L-Triptofán N-L-Formilkinurenin

N

CH2

CH

NH3+

COO-

O

H2

L-Kinurenin

triptofán oxigenáz

indukálható

O2Fe

Kinurenin formiláz

H2OFormiát

H2N

CH2

CH

NH3+

COO-

O

OH

Kimurenin

hidroxiláz

H2N

O

O-

OH

CH

NH3+

COO-CH3

H2O

3-hidroxi antranilát3-L-hidroxikinurenin

O2

Kinurenináz

PLP

3-hidroxi antranilát oxidáz

CH N

O

O-

O

OO-

2-Acroleil-3-aminofumarát

CH NO

OO-

HH

H

H3+ H3

+

CO2

2-amino cisz,cisz mukonátszemialdehid

CH2H

H

CO O-

COCO-

OOxalokrotonát

CH2

COCO-

O

O-OC -OOC

CH2

CH2

CH2

C

C

O-

O

O

NAD(P)H2

NAD(P)

CO2 + H2O

-ketoadipinsav

L-Trp - catabolism

Lack of Vitamin B6:Accumulation of Xanturenate

Hartnup disease: Autoszomal recessive disorderDefect of transport of neutral amino acids in the

intestine, kidneysAciduria of neutral amino acidsExtretion of degradation products – indol - of TrpBiosynthesis of Niacin is decreased – Pellagra like

symptoms

-ketoglutarát

szukcinil-KoA

fumarát

oxálacetát

citrát CC

L-glutamát

Arg, His, Gln, Pro

Ala, Cys, Gly, Hyp, Ser, Thr

Piruvát

Acetil-KoA

Ile, Leu,Trp

Leu, Lys, Phe, Trp, Tyr

Acetoacetil-KoA

L-Asp, L-Asn

Ile, Met, Val

Tyr, Phe

LysKetogenic

Lys-catabolism

-OOC

CH2

CH2

C

C

O

O-

OH2

NH+

CH2

CH2

CH2

CH2

CH

NH3+

COO-

L-lizin

-OOC

CH2

CH2

C

C

O

O-

COO-

NH3+

CH

CH2

CH2

CH2

CH2

NH+

H2O

NADH2

NAD

szacharopin-reduktáz

Szacharopin

COO-

NH3+

CH

CH2

CH2

CH2

CH2

NH+

O-

O

C

C

CH2

CH2

-OOC

2

COO-

NH3+

CH

CH2

CH2

CH2

CH2

NH+

O-

O

C

C

CH2

CH2

-OOC

NH+

O-

O

C

C

CH2

CH2

-OOC

3

COO-

NH3+

CH

CH2

CH2

CH2

C

O

H

L-Glutamát

L- -Aminoadipát- -semialdehid

H2O

L--aminoadipát

-ketoadipátGlutaril-CoACO2 + H2O

Lys-catabolism

Defect of saccharopin dehydrogenase:Autosomal recessive disorder

-ketoglutarát

szukcinil-KoA

fumarát

oxálacetát

citrát CC

L-glutamát

Arg, His, Gln, Pro

Ala, Cys, Gly, Hyp, Ser, Thr

Piruvát

Acetil-KoA

Ile, Leu,Trp

Leu, Lys, Phe, Trp, Tyr

Acetoacetil-KoA

L-Asp, L-Asn

Ile, Met, Val

Tyr, Phe

Catabolism of Met, Ile & Val

Metionin

Izoleucin

Valin

-ketobutirát

propionil-CoA

metilmalonil-CoA

szukcinil-CoA

Catabolism of Met, formation of active Met

COO-

C

CH2

CH2

S

CH3

H3+N H

O

OHOH

AdeninCH2

P P P

COO-

C

CH2

CH2

S

CH3

H3+N H

O

OHOH

AdeninCH2+

H2O Pi + PPi

L-metioninadenoziltranszferáz

L-Metionin

ATP S-Adenozil-L-metionin

L-Metionin

S-Adenozil-L-metionin

ATP

Pi + PPi

Akceptor

CH3-Akceptor

S-Adenozil-L-homocisztein

H2O

Adenozin

HSCH2

CH2COO-

NH3+

CH

L-homocisztein

-OOCCH

NH3+

CH2

OH

L-szerinH2O

cisztationin--szintáz

CH2

CH2COO-

NH3+

CHS

CH2

NH3+

CH

-OOCCisztationin

S

CH2

NH3+

CH

-OOC

H

CH2

C

COO-

O

CH3

H2O

NH4+

L-cisztein -ketobutirát

NAD

NADH2

CoASH

CO2

CH2

C

O

CH3

S-CoA

Propionil-CoA

Catabolism of Met, formation of active Met

A Met katabolizmusa: az aktív Met képződése

L-Metionin

S-Adenozil-L-metionin

ATP

Pi + PPi

Akceptor

CH3-Akceptor

S-Adenozil-L-homocisztein

H2O

Adenozin

HSCH2

CH2COO-

NH3+

CH

L-homocisztein

-OOCCH

NH3+

CH2

OH

L-szerinH2O

cisztationin--szintáz

CH2

CH2COO-

NH3+

CHS

CH2

NH3+

CH

-OOCCisztationin

S

CH2

NH3+

CH

-OOC

H

CH2

C

COO-

O

CH3

H2O

NH4+

L-cisztein -ketobutirát

NAD

NADH2

CoASH

CO2

CH2

C

O

CH3

S-CoA

Propionil-CoA

Homocystein metabolismus

Catabolismus of Met, Ile & Val

Metionin

Izoleucin

Valin

-ketobutirát

propionil-CoA

metilmalonil-CoA

szukcinil-CoA

Catabolism of branched chain amino acids

Leu, Val, Ile

transzamináz reakciók

A megfelelõ -keto-savak(-keto-izokaproát, -ketoizovalerát, -keto--metilvalerát)

CO2 megfelelõ Acil-CoA tioészterek

Megfelelõ -telítetlen

acil-CoA tioesztérek

-hidroxi- -metil-

glutaril-CoAszukcinil-CoA

propionil-CoA

acetil-CoA

elágazó szénláncú a-ketosav dekarboxiláz

(marple syrup urine disease)

(izovaleriánsavas acidémia)

ValLeu

Ile

NH2 CH COOH

CH2

CH

CH3CH3

NH2 CH COOH

CH

CH2

CH3

CH3

NH2 CH COOH

CHCH3CH3

O C COOH

CH2

CH

CH3CH3

O C COOH

CHCH3CH3

O C COOH

CH

CH2

CH3

CH3

CO2 CO2 CO2

O C

CH2

CH

CH3CH3

S KoA O C

CHCH3CH3

S-KoA O C

CH

CH2

CH3

CH3

S-KoA

O C

CH

C

CH3CH3

S KoA O C

C

CH2CH3

S-KoA O C

C

CH

CH3

CH3

S-KoA

Leucin IzoleucinValin

-ketoizokaproát -ketoizovalerát -keto--metilvalerát

-ketosav -ketosav -ketosav

-aminosav -aminosav -aminosav

KoA-SH KoA-SH KoA-SH

Izovaleril-KoA Izobutiril-KoA -metilbutiril-KoA

-metilkrotonil-KoA Metakrilil-KoA Tiglil-KoA

2 [H] 2 [H] 2 [H]

Transzamináz

-ketosavDH