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PPP/HMP Shunt

OVERVIEW OF METABOLISM
TYPE 2 GSD = Pompes disease
df @ -1,4-glucosidase (acid maltase) @ All organs (enzyme is in lysosomes).
Progressive muscle weakness.
Breathing and feeding difficulties.
Hyporeflexia or areflexia due to glycogen accumulation in spinal motor neurons.
Cardiomegaly leading to congestive heart failure
death before the age of 2

Galactitol

Galactose

Non-reducing
End

Non-reducing
End

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1~OH)

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1~ O

Non-reducing
End

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1~OH

DEBRANCHING ENZYME (Tranferase Activity)

HO~4-Glu-1~ O

Non-reducing
End

The transferase activity removes the terminal 3 glucose residues of one branch
and attaches them to a free C-4 end of a second branch.

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-(4-Glu-1)~(4-Glu-1)~(4-Glu-1)
The glucose in -(1,6)-linkage at the branch is then removed by the action of glucosidase.
This glucose residue is uncharged

+ Glucose

-Ketoacids
Amino Acids (NH3)

CO2 + PEP

UDP-GAL-4-EPIMERASE

Non-reducing
End

Glucose

Pyruvate

Alanine (NH3)

Glu(NH3)

-KetoGlu

NH4 + CO2

NH2
C Carbamoyl Phosphate
OPO3

Liver Mitochondria
Cytoplasm

MALATE-DH

Ornithine

UREA
CYCLE

Urea

H2O

DHF

Transamination

PDH

CO2 + ATP
Acetyl-CoA
PYRUVATE
CARBOXYLASE
Mg

HIGH
ATP + Acetyl-CoA
State favors the
PC Reaction > PDH Rxn
in the liver

LDH recycles NAD under aneurobic condition


so we can continue Glycolysis and produce 2ATP/Glucose

ATP
Acetyl-CoA
NADH

Phenylalanine
Aceto-Acetyl-CoA

Acetyl-CoA Isoleucine

Leucine
Lysine
Tryptophan
Tyrosine

ATP

CITRATE
SYNTHASE

ADP + pi

NAD
Asp + aKG Glu + OAA

Asn + Glu Gln + Asp


ATP

cis-aconitate

TCA

Fumarate
Fumerate
Phenylalanine / Tyrosine

I-DH = ADP (low E state)


I-DH = ATP & NADH

Succinyl-CoA
NADH
ATP

Succinyl-CoA

CO2 + NADH

-KG

Oxidative Deamination of Glu

GLUTAMATE-DH

NADH
NH4

Glutamate Derivatives

Heme

NAD

+Fe
Proto-Porphyrin

Co-Pro-Porphyrinogen

Uroporphyrinogen III

Reduction of AKG to Glutamate


Decarboxylation of Glutamtate to GABA
Amination of Glutamate to Glutimine
Reduction of Glutamte to Glutamate to Glutamate Semialdehyde
Tranglutamination of Glutamate Semialdehyde to Ornithine
Ornithine can enter the UREA CYCLE and produce Arginine
Spontansouse Cyclization of Glutamate Semialdehyde to Proline 5 Carboxylate
Reduction of Proline 5 Carboxylate to Proline

IPP + DPP

GPP + IPP

FPP + FPP

Squalene

Cholesterol

All AAs + aKG

TRANSAMINASES

+ Ergosterol

Hormones
Bile Acids
VitimainD

OH~ C3~Carbon

OH~ C3

Sphingosine

|
OH~ C2
|
OH~ C1

~Carbon Chain
~Carbon Chain

Glycerophosphlipids

C3 ~ester
|
C2 ~ester
|
C1~OPO3

Chain

NH2~ C2
|

OH~ C1

OH~ C3~Carbon

Chain
|
C2 ~amide~Carbon Chain

Sphingomyelins

OH~ C3~Carbon

Chain
~Carbon Chain
~Sugar

Glycophinolipids

|
C2~amide
|
C1

OH~ C3~Carbon
Ceramides

|
C2 ~amide
|
C1~OH

Chain
~Carbon Chain

GABA: Via Glutamate Decarboxylation

+ NADPH + H Glutamate y-Semialdehyde Spontaneous Proline-5-carboxylate + NADPH + H Proline


Glutamate

Cyclicization

~Choline

|
C1~OPO3

~Choline

KetoAcid + Glu

ATP & NH4

Glutamine

To Urea

Cycle
CO2 + NADH

+
Glycine
ALA SYNTHETASE
ALA
(Regulated Step)
-Amino-Levolinic Acid (ALA) Mitochondria

Cytoplasm
Porphobilinogen

Pre-Uro-Porphyrinogen

HMG-CoA Reductase Mevalonic


Acid + NADP+

Phe PHENALALANINE HYDROXYLASE Tyr TYROSINASE Melanin

TERTRAHYDROBIOPTERIN
*Albinism
here
Homogentisate
*PKU here

HOMOGENTISIC ACID OXIDASE


*Alkaptonuria here
fumarylacetacetate

fumarate

TCA

Isocitrate

KG-DH

Iso, Met, Thr, Val Succinate

GTP + CoA

Malonyl-CoA

ISOCITRATE-DH

+ Acetyl-CoA + 2NADPH

(Niacin = B3, Serotonin = 5HT, Melatonin)


(Catecolamines, Melanin, Thyroxine)

Inhibits PFK
Citrate Citrate
favoring Gluconeogensis

OAA

FADH2
Arginine

+ ADP

CYSTATHIONE
SYTHASE

NADH MALATE-DH
Malate

Fumerate

ATP +

N5N10-M-THF + Glycine Serine + THF

ATP + CO2

NADH

Malate

Argino-Succinate

OT

(Reducing End
with a free OH)

to UREA Cycle

NH4

Oxidative Deamination

OAA

Citrulline

UDP-Gal

(Reducing End
with a free OH)

GDP
PEP-CARBOXYLASE
GTP

Aspartate

1 ATP Used (Net = -1)

Glu-1P PHOSPHOGLUCOMUTASE

GAL-1P
URIDYL0TRANSFERASE

OPPiO-Uridine

6OH

GLUCOSE
ALANINE CYCLE

ORNITHINE
TRANSCARBAMYLASE
Ornithine + Carbomyl Phosphatate Citrulline

HEXOKINASE

NUCLEOTIDE
PRECURSOR

G3P

DEBRANCHING ENZYME (GLUCOSIDASE ACTIVITY

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-(4-Glu-1)~(4-Glu-1)~(4-Glu-1)

Gal-1P

4-Glu-1-

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1~OH)

(Reducing End
with a free OH)

ADP

+ ATP GALACTOKINASE

(Reducing End
with a free OH)

Type 5 GSD = McArdles disease

@ Myophosphorylase @ Muscle.
PHOSPHORYLASE dfMuscle
weakness and cramps after exercise

Myoglobinuria (burgundy urine) after exercise


G1P (+ Glygogen -1)

PHOSPHOGLUCOMUTASE

G6P

TYPE 3 GSD = Coris disease


df @ Debranching enzyme (-1,6-glucosidase) @ Muscle and liver.
Similar to type I without lactic acidosis
Hypoglycemia
Hepatomegaly
Delayed (ultimately normal) growth.
DEBRANCHING ENZYME
Symptoms usually regress in adulthood
Non-reducing
End

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1~OH)

Aminoglucotransferase (branching enzyme)

(4-Glu-1)~(4-Glu-1)~(4-Glu-1)~(4-Glu-1~ O

pi + Glucose
G6-PHOSPHATASE
#1
H2O +

Irreversable, important in Regulation


AKG-DH
Citrate Synthase
Pyrivate Kinase
PFK
Hexo/Glucokinase

T
G6P
UDP-Glucose
GLUCOSE 1P
#2 PHOSPHO-GLUCOSE ISOMERASE
URIDYL TRANSFERASE
+
Fructose
GLYCOGEN SYTHASE +
pi
+
F6P ATP
(4OH-Glu-1)~(4-Glu-1)~(4-Glu-1~OH)
F1P
(F26Bisphosphatase) [cAMP] Glucagon
= F6P, AMP, F26BP
F1,6,BISPHOSPHATASE #3 PFK PFK
PFK = ATP, Citrate
ALDOLASE B
1 ATP Used (Net = -2) Glucagon/cAMP inhibit PFK
F2,6BP AMP F1,6BP
(F26Bisphosphatase)
DHAP
+
Glyceraldehyde
+ NADH Glycerol + NAD

H2O + F1,6DP ADP

Glucagon [cAMP] Glucagon/cAMP activate F16BPase


Glycerol
G3P

TRIOSE
KINASE
#4 ALDOLASE

TRIOSPHOSPHATE ISOMERASE
Hb
NAD G3P #5 TPI DHAP
GLYCEROL KINASE
G3P
METHEMOGLOBIN REDUCTASE #6 GLYCERALDEHYDE-3-PHOSPHATE DH
G3P Serine
Glycine
CO2 + NH4
1NADH Produced x2 = 2NADH
Met-Hb
NADH 1,3DPG
N5N10-methylene
THF N5N10-methylene
THF
THF
23BPG DIHYDRO-GLYCERO-MUTASE
+H2O
THF
MUSCLE

#7
PHOSPHO-GLYCERATE
KINASE

23BPG DPG PHOSPHATASE


N5N10-M-THF + dUMP THYMIDILATE SYNTHASE DHF + dTMP
1 ATP Produced x2 = 2ATP) (net = 0ATP)

3PG

DIHYDROFOLATE
REDUCTASE
via SAM CH3
TTMP
#8 PHOSPHO-GLYCERO-MUTASE
LIVER
to Muscle
*MTX,
METHIONINE
Methionine
Homocysteine + Serine + B6
Cystathione Cysteine

Alanine (NH3)
Glutamate (NH3)

SYTHASE
2PG
Glucose
Vit-B12

dTTP
#9
ENOLASE
THF
CH3-THF
Pyruvate Gluconeogenesis
aKG
PEP
PK = F1,6BP activate
#10 PYRUVATE KINASE PK = Alanine + cAMP Glucagon inhibit favoring Gluconeogensis
1 ATP Produced x2 = 2ATP (net = +2ATP)
Ala, Cys, Gly, Ser, Thr Pyruvate + NADH LACTATE-DH Lactate + NAD
ALDOSE REDUCTASE

Non-reducing
End

TYPE 1 GLYCOGEN STORAGE DISEASE = Von Gierkes disease


df @ Glucose-6- phosphatase @ Liver and kidney.
Severe fasting hypoglycemia
Lactic acidosis. Hepatomegaly (100%)
Short stature (90%). Delayed puberty.
Bleeding diathesis (especially epistaxis).
Hepatic adenomas (75%)
Renal failure and gout in 20s and 30s.

G6P
2GSH + HOOH
NADP + 2GSH
oxidative
G6P-DH
Glutathion Reductase Scavanging
phase
NADPH + GS-SG
GS-SG + 2H2O
6-Phospho-gluconolactone

GLUCONOLACTONASE

6-Phospho-gluconate
NADP
6PHOSPHO-GLUCONATE-DH
NADPH
R5P
( xylulose )
R5P-ISOMERASE R5P-EPIMERASE
R5P

TRANSKETOLASE
TRANSALDOLASE non-oxidative
TRANSKETOLASE phase

G3P + F6P
FRUCTOKINASE

Essential AAs
PVT TIM HALL
Phe
Val
Thr
Trp
Ile
Met
His
Arg
Leu
Lyse

+ Glutamate

Ornithine + KG

UREA CYCLE

Non-Essential AAs
Ser, Cys, Gly
Ala
Asp, Asn
KG + NH4 + NADPH + H
Glu, Arg, Pro
Tyr
Non-Essential AAs
3PG --> Ser Cysteine Gly
Pyruvate --> Ala
AKG --> Glu, Arg, Pro
Phe --> Tyr
OAA --> Asp --> Asn

Glutamate Derivatives
Glycine
Arginine
Histidine
Prolone

Arginine Creatine, Urea, NO

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