Glycoloysis

Glycolysis
EMP
EMPPATHWAY
paway
FED State >
insulin ; catabolic pathway occ.in cytoplasm
occurs in ALL cells

ONLY pathway in both aerobic + anaerobic > glucose : ONLY molecule to produce ATP
without 02

ENERGY UTILIZATION PHASE :

>
1st committed step .

ATP ADP ATP ADP

-1 7

glucose > GGP FGP

-12 "
hexokinase ; Mg isomerase PFKI ;↑4g
"

G3P + DHAP FI ,6bP

1-
-
aldolase A

ENERGY PRODUCING PHASE : isomerase

"
NAD NADH ADP ATP
7

G3P- I ,3bPG >

-12
3PG <
G3P dehydwg .

; Pi phosphoglycewkinase ; Mg
isomerase

ADP ATP H2O \

7 1-
pyruvate < PEP ZPG
COO
-

pyruvate kinase
-

O -
C=O ge -

O -
C -0
1 1 I
C=O
kt C -
O -
P H - C -
O -
p
I 11 1
C C HO -
C
 Important points : DHAP >
also used for TG synthesis

glucose >
GGP : flux generating step ; high reaction velocity + bow km

HK

FGP 1--2,6 BP rate

> :
limiting step ; low reaction velocity +
high km

PFKI ( bottleneck ) and also 1st committed step

aldolase B : hepatic isoform ; in fructose metals .

1st REDOX reach : G3P dehydro -

arsenate Cl
g. <
:

and the ONLY redox reaction in glycolysis . iodo acetate : NCI

ANAEROBIC GLYCOLYSIS : seduction

+
NADH NAD
7

pyruvate lactate dead end in

glycolysis
,,☐µ-
>

COOH COOH
1 I
C. = 0 C- OH
I 1
C C

-
 AEROBIC SLP 4 ATP
Energetics of Glycolysis >
: >

used > 2 ATP 7 ATP

u 2 NADH > 5 ATP

ANAEROBIC : SLP > 4 ATP 2 AM

used >
2 AM

Cori’s Cycle
muscle
exercising > anaerobic glycolysis
muscle liver

glucose < glucose

"

gluconeogenesis
11

pyruvate pyruvate
"
LDH LDH

✓ blood

lactate > lactate

/
GLUCOKINASE : HEXOKINASE :

↑↑ Vmax t.fi Vmax

↑↑ km It km
,

@ liver ; B islet cells @ most tissues

not inhibited by GGP inhibited by GGP

inducible not inducible

t.lv levels in DM deficiency > hemolysis

mama, ,, , , ,µ. . a m . mama,
www.gw.g.am
 Rapaport-Leubering (or) RL Shunt
10% of glucose in RBC : enters RL shunt , bypasses an SLP reaction

in RL shunt : no ATP ie within the shunt

1,3 BPG
mutase

ADP phospho glycero kinase u

-12
Mg 2,3 BPG > releases 02 from
AIP <
HBA ONLY

× Pi 1-120 . . . . . . . . . . .
:
^

3 PG <
× ÷

2,3 BPG phosphatase : hydrolase

2,3 BPG : releases 02 from HBA only it binds only to B chain

- .

Inhibitors of Glycolysis
COMPETITIVE INH .
: NON -
COMPETITIVE INH .
:

arsenate : G3P dehydrogenase iodo acetate : CBP

dehydrogenase
Oxamale : LDH Na F : enolase

arsenite : PDH ;

glycolysis continues even in presence of 175+5 (175+3) ✗ -

ketoglutarate dehydrog.
( arsenate )
> but there is a loss of > ATP
 "

NO NADH >

NO SLP

v >

.
'
. loss of > ATP _

'
NAF : blood glucose estimation

Regulation of Glycolysis
PFK -1 : only allosteric modulation v15 pyruvate kinase

ENZYME REGULATION ACTIVATORS INHIBITORS

PFK -1 allosteric modulation 1=2,6 BP : most potent citrate ; ATP

ADP

pyruvate kinase allosteric + 1=1,6 BP phosph .

state

covalent modif . dephosph . state v

u
glucagon
insulin

1-IONOTROPIC modulators substrate substrate ATP ; 1--2,6 BP in

: -
regulate : glycolysis
HETEROTROPH : other than substrate > citrate in glycolysis
INSULIN + PFKII F- 2. Gbp
> >

dephosphorylation

+
FGP

PFKI <

f- 1. Gbp .
PFKII : bifunctional
+ "

v PFKII +

pyruvate kinase f- 2GBP tase -

Linkreaction
Link reaction
location of reaction : Mt matrix
.
; location of PDH : IMM

"
CoA NAD NADH
-
,
req Of oxid decarboxylation
. .
:

pyruvate i
> acetyl CoA
.
By : TPP
° °
11
PDH complex
"
11
-
Bz : FAD

c- c- COOH
•
coz C -
C -
S -
CoA .
Bz : NAD
•
Bg : CoA

PDH complex : pyruvate dehydrog .

-

lipoic acid
-13
dihydwlipoyldehydrog .
<
-
As

dihydrolipoyl transacetylase _
 PFK -1 :
only allosteric mod .
PK : both allosteric + COV .

PFK -2 only covalent

Important points : mod . mod .

> @ IMM
I
pyruvate formed in cytoplasm >
enters mitochondria by pyruvate H+ symport -

PFK 11 :
bifunctional enzyme E activities of 2 enzymes : phospho truck kinase 11

v > activated by insulin by dephosph . 1=2,6 bptase

NO allosteric modif .
( covalent modification )

Fate of G6P > glycolysis : i /40 activated PFKI ; pyruvate kinase

> glycogenesis : i /C /0 deactivated PFKI ; pyruvate kinase

> HMP pathway

AEROBIC COOH C CoA

Fate of Pyruvate : C C C S
- - - -
-

> >

pyruvate acetyl CoA

v

ANAEROBIC v

\
TCA cycle
v u

I step fermentation : 2 step fermentation :

pyruvate > lactate pyruvate > acetaldehyde

LDH
0
•-•,OH decarboxylase ×

C- & -

COOH >
C -
C -
COOH 0 % ethanol
^
11
C -
C -

Coot, > C- CHO >

C -
C OH
-
 Regulation of Link Reaction
link reaction : irreversible

pyruvate :
mainly derived from carbs .
: fats can never be converted to carbs

acetyl CoA : mainly derived from fats

✓

except 2
products of TG breakdown :

glycerol glucogenic
-

>

propionic acid
-
_

Regulation of PDH

\/ \/

ALLOSTERIC END -
PRODUCT INHIBITION : COVALENT MODIFICATION :

acetyl CoA fed state >

insulin

NADH pyruvate dehydrog.

-

>

ATP "

PDH active in dephosph state .

PDH complex Deficiency >

MCC of congenital LA

-
XD
-
MCC of congenital tactic acidosis
-
brain : sensitive to acidosis > neuro
degen .
; spasticity ; early death
•
Px : no specific Px > carbohydrate restriction + 131 supplement
 Kreb’s
Kreb’s cycle
cycle
"
TCA cycle ; citric acid cycle : .
amphibolic > Oxidative +
synthetic react

-
activated by neither ; both fed +
fasting
'
in mitochondria ; in all cells c- mitochondria

only in aerobic condn

-
all enzymes in mitochondrial matrix except SDH
TCA cycle depends on 2 factors : @ IMM <

energy status of cell

-

'
availability of 017A >
OAA : carrier

1st substrate in TCA cycle

SOURCES OF OAA : catalytic role
A.

CO2 ; ATP ; By
pyruvate s
>
OAA .
pyruvate carboxylase @ mitochondria

pyruvate carboxylase
0 0 A : ATP
11
> req .

11
C- C- COOH > HOOC -
C -
C -
COOH B :B > biotin

C : CO2
B.

aspartate ketoglutarate glutamate

iagg.gg#OAA
+ ✗ +

COOH COOH COOH COOH

I b- I 1 I
C- MHz c=0*• # c=O C- MHz
I + 1
I + I
transaminase
c c c
c
I 1 1
I
COOH C
COOH C
I
1
COOH
COOH
1. CONDENSATION STEP : citrate synthase : transferase
rate limiting
OAA citric acid +
acetyl CoA +
>
COOH citrate synthase HOOC C irreversible
f
-

I 1
S CoA
☆
☐ = C - -

OH
c=o HOOC -
C -

1 I

& HOOC -
C

COOH

2. aconitase : lyase ( not an isomerase ) ; aconitase >

Fe -

containing enz .

citrate isocitrate
_
HOOC -
C -
aconitase HOOC -
C -
OH
I

HOOC -
C -
OH HOOC - {
I 1

HOOC -
C HOOC -
C

3. OXIDATIVE DECARBOXYLATION : 2 consecutive oxidative decarboxylation

-

NAD NADH ncoz

isocitrate
7
) ✗ -

ketoglutarate
" 00C -
C -
otiisoa.ba/edehydwgenage- COOH
I
rate
1
HOOC -
c • oxidised
c=o limiting
l v I
HOOC -
C -12 -12 C
seq Mg or Mn
,
• .

coz
C
1

COOH -
4. OXIDATIVE DECARBOXYLATION :

NAD NADH coz

> ✗

d-
ketoglutarate > succinyl CoA rate

✗ KG
COOH dehydrogenase + COA 0=C -
s -
CoA limiting
1 ^ I
oxidised +

4=0 f
→

• irreversible
C
{
coz -13
As
,
C COOH _

COOH

5. SLP : thiokinase :
ligase
GDP GTP CoA

%inag#-
→ ,

succinyl CoA succinate

0 = C -
S -
CoA COOH
I 1
C C
1 • I
high energy bond
C
c
1
I
COOH
COOH

6. OXIDATION ONLY

FAD
_
FADHZ
succinate fumarate
COOH _g☐ COOH
I 1
C C
'
11
f f
COOH
COOH
7. HYDRATION STEP : fumarase : lyase
1-1+01-1
-

fumarate malate

COOH fumarase COOH

I 1
C
C- OH
"
l
C H
C -

I
1
COOH
COOH

8. OXIDATION ONLY

NAD NADH
-1

malate \ OAA

COOH
I
_ma1a1edehydW9eⁿÉ COOH
1
C- OH C=O
I • oxidised 1
C C
1 1
COOH COOH

Energetics of TCA cycle

I acetyl CoA > NADH : 3 >
7.5 ATP

FADI-12 : I > 1.5 10 ATP

SLP : I >
1

no -

of oxidation reactions : 2 oxid.de carb .

> 2✗ NADH

2 only Oxid .
> I ✗ NADH 1- 1 FADHZ
1 glucose > 7+5+20 ATP : 32 ATP

v v v

glycolysis : > ATP link reaction : 5AM TCA cycle : 20 ATP

NADH : 2 > 5 ATP NADH : 2 >

5- ATP NADH : 6 >
15 ATP

SLP : 4 > 2 ATP FADHZ : 2 3 ATP

ATP used : 2- SLP : 2 ATP

Regulation of TCA cycle

Rate Limiting Enzymes Irreversible Steps

-
citrate synthase .
citrate synthase
-
isocitrate
dehydrogenase .
✗
ketoglutarate dehydrogenase
-

-
d-
ketoglutarate dehydrogenase

PDH : also regulates TCA especially in BRAIN

↑ ATP activates TCA ↑ ADP

↑ NADH inhibit TCA cycle < cycle TNAD

a

↑ succinyl CoA

i.
'

. . "

> indicate HIGH ENERGY state indicate LOKI ENERGY state

 Mechanism of Flouro-acetate and Flouro-citrate inhibition of
Aconitase

f-louro acetate - acetate > flown acetate + CoA

11

f-Louro acetyl CoA

replaces acetyl CoA

OAA +
f-Louro acetyl CoA > f-louro citrate

competitively inhibits aconitase

 TCA cycle final pathway for oxidation of carbs ; lipids protein
-

> common ;

}
as
glucose
fatty acids are metals . to acetyl CoA (or ) TCA interned .

amino acids

hyper NHq
-

emia : depletes ✗ -
KG levels

\/

binds to glutamine
> excess NH
} glutamate >

=
↓ ↓ glutamate levels
v

compensated by amination ✗ KG
of glutamate
-

>
 Inhibitors of TCA cycle

v v

CI : NCI :

flourocilrate aconitase flownacetate aconitase

- - -
'
> >

malonale SDH ✗ KG dehydrog.

-
arsenite
-
- .
> >

MALO NATE : 3C ; inhibits SDH ; ETC -

complex 11 ; carnitine palmitoyl transferase 1

flouroacetak : plant toxin ; used in pesticides

✓

enzyme in 13 oxdn of
-
FA

i
carrier of TCA cycle : 017A .

acetyl CoA : not an intermediate of TCA

'
1st substrate of TCA : 017A never glucogenic

Glycolysis inin
Glycolysis
cancer
Cancer cells
ces

Pasteur’s Effect > normally occurs in all cells .

if Oz ✓ anaerobic ↑ 02 ↑ ATP ↑ citrate

-
PFKI
-

> glycolysis ; >

+
>

PFK I -
: allosterically activated by 1--2,6 BP ; inhibited by ↑ ATP ; citrate
 CA cells PARADOX
Warburg’s Effect >
Occurs in ; :

lactate
even in presence of Oz :
glucose >

v v aerobic glycolysis
aerobic glycolysis

.
: in CA cells : aerobic glycolysis c- lactate as end product
9-
glucose :
only 2 ATP

Shules
Shuttles
to move substrates b/w mitochondria ; cytoplasm

Malate-Aspartate Shule
OUTLINE :
> more important in :

aspartate < aspartate HEART

"
LIVER

OAA 017A
^

malate > malate

CYTOPLASM MITOCHONDRIA

IMM
 aspartate , aspartate
✗ -

ketoglutarate ✗ -

ketoglutarate ,
^

SGOT SGOT

v
glutamate glutamate
OAA OAA
"
NADH NADH
t

malate malate

dehydrogenase > NAD NAD dehydrogenase

"

malate >
malate

1. cytoplasm 11%941 2. mitochondria

Glycerol-PO4 Shule
BRAIN ; 5K MUSCLE
.

1. 2 .

C- OH C- OH
1 I
DHAP <
DHAP
c=O c=O
I 1

C -
O -

Poa C -
O -

Poa
^

glycerol -
3P NADH FADHZ , glycerol 3P
"

dehydrogenase red
dehydrogenase
× > NAD FAD

c- OH C- OH
1 I
G-0131° ← G- 01313
c- OH > c- OH
I 178$11 I
C- 0-1204 C -
O -

Poa
 Citrate Shule
to transport acetyl CoA from mitochondria > cytoplasm for FA synthesis
( formed by LINK REACTION

citrate <
citrate < 01717 +
acetyl CoA
^
citrate synthase

citrate lyase
✗

acetyl CoA + 01717

"¥1m
>
used for FA synthesis
☆ 1. mitochondria

2. Cytoplasm

Creatine-PO4 Shule
to move ATP from mitochondria > cytoplasm ; CK : creatine kinase

CYTOPLASM ATP + creatine <

ADP + creatine Poa
1-

cyt .
CK

IMS ATP + creatine

.

→
ADP + creatine Poa
1-
mt CK .

Mt . MATRIX ATP
.

AtP☆g☆&FFEfffg
↳O☆%% ✓

App
^
-

atractyloside
 Electron
Electron
transport chain
Transport Chain

Components of ETC
5 protein complexes : I -
V I -111 inv in e- transport ;
V : ATP synthase
,
.

coenzyme Q ubiquinone > Only non -

protein comp .

cytochrome C ,
not lying in IMM

⑧
-

H : hydride → + •
2é 111 : cyt oxidase
.

> HEMO PROTEIN i. e

H+ : proton has heme as prosthetic group

drug : oligomycin
flow of electrons cyt -
C
-

"
FMN + Fe s
-

1-
> Cu
,
I ^ 111 111 V

11 Q cyt -
B ;C

Fe s-

FAD + Fe -
S V

O
2
flow of e- occurs due to REDOX potential > tendency to gain e-
i. ETC : redox potential ↑↑ in the direction of flow of e-

i. redox potential of NADH : minimum

of Oz : maximum

+ +
a
41-1 41-1-1, a
21-1

-12e-

2€
-

1- L

NADH NAD
-

2C
+ -1 +
41-1 41-1
1/202
+
1 NADH
gives hydride ion to cmplx I 41-1-1 > 21-1-1 + 21-1-1
-

H : 2 e-

INADH gives 25 for e- transport

-

. . v

4 H+ H2O
_

2C pump out

through 1 41-1-1 101-1-1

-

INADH
- '
2C : : . .
= 2C =

+
111 : 41-1
+ "
111 : 41-1-1 >
21-1++21-1 ,,
for H2O prod
 +
41-1 21-1-1
^ ,,

=
. ✓

" e-
-

2C
s
2é
^

FADHZ FAD v

41-1-1
-

Ze
+
+
I FADH,
-

= 2e = 41-1

4202
+
through complexes 11 H movement
-

Ze : no +
+
111 : 41-1 41-1-1 >
21-1-1 + 21-1-1
111 : 21-1-1 '/

.
-

.
IFADHZ : 61-1-1 H2O

+
movement of 41-1 from IMS to matrix = 1 ATP
+
.
'

.
I NADH : 101-1 : 2.5 ATP

1 FADHZ : 61-1-1 : 1.51717

ADP -
ATP TRANSLOCASE : @ IMM ; flip-flop mechanism to transfer ATP into IMS
-1
and ADP into Mt . matrix
-

atraclyloside

ADP -
ATP translocase : seen in creatine -
P shuttle ; to move ATP from mitochond .

to cytoplasm
 Uncoupling of ETC
coupling reaction : OXIDATIVE PH RYLATION
.

v v

flow of e- ATP formation

UNCOUPLING : oxidation c- out ph.ir/lation

UN COUPLERS : subs .
that create HOLE in IMM > uncouple ETC

H+ use the hole instead of C- 11 to return to mt matrix

.

in the presence of
THE RMOGENIN protein @ BROWN FAT , NO PH RYLAN ON
.

NO ATP

+
to H movement
energy produced due
the

is diverted for heat production

called as NON -
SHIVERING THERMOGENESIS

other uncouples . > DRUG : dinitro phenol

> PHYSIOLOGICAL :
thermogenin LC FFA

thyroxine
 Inhibitors of ETC

COMPONENT INHIBITORS

1 : NADH
dehydrogenase rotenone ; piercidin A : insecticides

phenobarb ; amobarb : barbiturates

11 : succinate dehydrogenase malonale ; Carbo ✗ in fungicide

ITFA

111 : cyt -

c reductase phenformin ; BAL : dimercaprol

111 : cyt -

c oxidase CO ; CN ; Has ; NaN }

uncouplers dinitro phenol

thermogenin ; thyroxine ; LCFFA

V : ATP synthase oligomycin

ATP -
ADP translocase atrackloside

phenformin : oral biguanide hypoglycemic drug

>
ETC -111 > NADH ace .
>
↑↑ pyruvate redn > lactic acid

Hyperuricemia :
competes c- urine excr -

of uric acid
<
lactic acidosis <
 MELAS

MELAS : mitochondrial encephalopathy + lactic acidosis + stroke -

like syndrome

due to ETC -

complex 1 IV deficiency

IUSCOPY : modified GOMORI TRI CHROME staining of muscle

shows ragged reb fibers

 Gluconeogenesis
Gluconeogenesis
catabolic process > Occurs in starvation >
activated by glucagon
organelle : mitochondria + cytoplasm
( begins )

organ : liver > 90%

kidney > 10.1 .

FASTING STARVATION : preferred fuel > fats

adipose tissue > FFA > liver > B- Oxdn Of FA > releases acetyl CoA

V v v

fate 1 : TCA cycle fate 2 : KB synthesis activation of 1st step

of gluconeogenesis

Schema of Glycolysis & Gluconeogenesis

MITOCHONDRIA

glucose ,

hexokinase acetyl CoA

^
GGP tase ER
+
-

GGP .
× PDH
^
isomerase carboxylase pyruvate
^

" L

FGP ,
017A

PFKI f- 1GBP tase -

CYTOPLASM PEP
7
^
✓

<
FI ,6bP '
>
G3P< > 1,3 BPG 3PG ? > ZPG <

aldolase A dehydwg .
phgly .
Kinase isomerase enolase
FASTING STARVATION :

1. in mitochondria + activated by acetyl CoA :

CO2 ATP ADP

-

pyruvate >
>
01717 ( cannot cross IMM .
.
: OAA > malate )
py .
carboxylase ; B>
^
COOH COOH
I + I
C. = O C = 0
1 1
acetyl CoA
C
f
- COOH
2 . <

PDH NADH

mt .
malate
dehydrogenase
1-
NAD

reduction malate ( crosses IMM + enters cytoplasm

COOH HAD

d-
{ -
OH
1
cytoplasmic malate > NADH
{ dehyrogenase v

COOH
3. in cytoplasm : OAA

malate > 01717 COOH

I
C = 0
I
c
l
COOH
4. in cytoplasm ; OAA >
PEP i. e decarboxylation +
phrylation
carboxy kinase

GTP GDP
7 nC°2
017A PEP OAA
>

PEP carboxy -
kinase Poa donor : GTP

COOH COOH GTP v

I I
PEP
C. =D C -
O -
p
I • It 1-
GDP
C C
, •
CO2
COOH

5. to 9 . PEP-zo-i.FI ,
GBP

10 ; 11.
.

Pi
^

F1 , Gbp >
FGP > GGP
f- 1. Gbptase isomerase

FINAL 517=-1? in ER >

contains enzyme GGP tase :
-

Pi GGP enters ER via transporter T1

e.

GGP > glucose

GGP tase
-
"

in ER lumen : GGP > glucose + Pi

v via

enters cytoplasm via transporter T2 : GLUT -7 transporter 1-3

 RLE of Gluconeogenesis >
.
pyruvate carboxylase : pyruvate > OAA
-
PEP carboxy kinase : 01717 > PEP
-
FI ,6bP Ease -

3C compounds good substrates

Substrates of Gluconeogenesis : :

✗ V V V V V

pyruvate lactate glycerol propionic acid TCA interned .

glucogenic AA

1.

lactate
# pyruvate > gluconeogenesis
LDH

COOH COOH
1 I
C- OH C =D
I
1
C
C

2-

glycerol , glycerol 3P >

DHAP >
G3P

glycerol kinase glycerol 3P isomerase

dehyd .

C- OH C- OH
gluconeogen .

I 1
OH
G- c=0
I
C- O -
P
C -
O -
P
3 .
ATP AMP + Ppi ATP AMP coz
, _

propionic acid > propionyl CoA ,

, methylmalonyl CoA
thiokinase propionyl CoA

carboxylase
f f {
•

C > c > C- COOH

I 1 1
COOH 0 = C -
S -
CoA 0=C -
s - CoA

methylmalonyl
mutase ; 1312
v

gluconeogen .
<
OAA fo r succinyl CoA
TCA steps COOH
I
C
I
C
I
0 = C -
S -
CoA

4 .
AA ( total : 20 )
>

" " KETOGENIC

; KB
+ 5
acetyl CoA TCA interned ; .

pyruvate
GLUCOGENIC

v u

only KETOGENIC : 2 Only GLUCOGENIC : 13 v

'
leucine all the remaining P : phenylalanine
'
lysine AA 1 : isoleucine

T : tyrosine ; threonine

tryptophan
 Reciprocal Regulation
Of glycolysis +
gluwneogen .

FED State : INSULIN FASTING : GLUCAGON ; INSULIN ✗

+
" "

PFK -11 PFK -11 ✗

-11=2 Gbp
+
FGP ,

"

+ -

PFK I
-

< > fructose 1. Gbp _

tase : gluconeogen .

u inhibited

F1 ,6bP :
glycolysis continues

1=1,6 BP glycolysis
Fructose Mania >
:

1--1,6 BP tase
-

:
gluconeogenesis

1--2,6 BP : reciprocal regulator

f- 2. Gbp -
Ease : active in CA
 TIGAR : TP53 induced Glycolysis &
Apoptosis Regulator
TIGAR :
regulates glycolysis +
apoptosis in CA cells .

CA mutation

+
i.

p53 tumor suppressor gene

codes for
v

1753 protein + TIGAR

>

\/

f- 2. Gbp Ease
-

activity

1-

F2,bbP,,FGPg
activation of PFK I -

no further CA cells < glycolysis > repair of CA mutation

replication
CA cell apoptosis < fails <
 Glycogen
Glycogen
storage form of carbs +
energy

glycogen V. fats as
energy storage form :

-
fats cannot be metals .
anaerobically
'
fats > glucose >
blood
glucose levels cannot be maintained
'
fats cannot cross BBB

glucose mobilization faster E glycogen

'
:

Glycogenin > glycoprotein @ core of glycogen granule

primer glycogen synth

in
-
.

auto catalyst for att of to

glucose glycogen in
-
.

↑ H2
•

in has C C COOH attached to of tyrosine

glycogen glucose OH
- - -

×
¥
OH -
glu

GLYCOGENESIS ; GLYCOGEN 041515 : both @ cytoplasm

RLE : transferases
GLYCOGEN STORAGE : liver > tune .
: to maintain blood glucose
muscle > f- unc .
: contraction

brain
 Linkages in Glycogen
straight chains : ✗ 2 >
4

branching points ✗ I 6 glycogen synthase adds glucose

'
: >

GCHZOH
to non -

reducing end

1
OH
5
✗ -

glucose :
¢ ,
(✗ : -
OH downwards @ functional É )
3 2
OH

✗ (I > 4 :
CHZOH CHZOH
I I
O H H O H
+

-
OH OH -
OH

☒ 1-120

CHIH CHIH
"
H
non -

reducing Ca Cs C1 : free > reducing end

0
end

non -

reducing glu reducing glu

 Glycogenesis
FED State : INSULIN >
anabolic process @ cytoplasm of liver + muscle cell

glucose
ATP

hexokinase : muscle
glucokinase : liver
<
ADP v

GGP

mutase

"

GIP

UTP

UDP-glucose ph.sn/lase
'
2x Pi < Ppi v

pyroph tase
.

UDP-glucose

RLE regulatory
glycogen synthase : +

UDP-glucose is added to non -

reducing end of GLYCOGEN IN

i. e forms ✗ (I > 4 bonds

branching enzyme
v

adds branches : ✗ (I >

6) bonds
 Glycogenolysis
FASTING state : GLUCAGON > catabolic process @ cytoplasm in liver + muscle

( not mitochondria )

Minor Pathway of Glycogenolysis

-
I -

3% of glycogen is broken by minor pathway

.
@ LYSOSOMES
-

enzyme > acid maltase > >

POMPE 's disease : both glycogen -1
lysosomal storage disease

Major Pathway of Glycogenolysis

1. glycogen phosphorylase : RLE +

regulatory
breaks only ✗ (I →
4) bonds from non -

reducing end

Coen } . : PLP / 136 > phosphate donor

LIMIT DEXTRIN < until 4 glucose residues @ branch point

GIP
glucose released as

> phosphate donor : PLP

glycogen > limit dextrin + n GIP

glycogen ph rylase -

0-0-0-0-0-0-0
>
n ✗ PLP 90-1 .

glucose residues
2. glucan transferase : transfers 3 glucose residues from the pre v. chain to another

also : 4: a transferase chain

to expose ✗ (I →
G) branch pt .

0-0-10-0-0-0-0 • 0-0-0-0-0-0-0-0-0-0
> to
glucan
0
① transferase y 10-1
.

3. de branching enzyme : breaks ✗ (I >

G) > releases free glucose
( V. glycogen ph.in/1ase)
v > amy 101,6 glucosidase <

BI debranching
FUNCTIONAL :
glucan transferase +
activity
-

GIP from step . 2 is cony . to GGP :

LIVER : GIP >

GGP > free glucose released
mutase GGP tase
-

maintains blood glu .

MUSCLE : GIP > GGP > used by muscles for ATP

mutase generation > .
-

.
contraction

Q .
under anaerobic conditions ,
no .
Of ATP produced from glycogen 0 lysis :3

GGP anaerobic ATP SLP

glycogen ◦ lysis > > glycolysis : 2 <

1 ATP saved
 Common Enzymes

V X

glycolysis +
glycogenesis :
glycogenesis +
glycogen olysis :
hexo
glucokinase mutase v

glycogen olysistgluconeogen .

GGP tase
-

Regulation of Glycogen Metabolism

Catabolic state
"

+ ↑↑ CAMP
FASTING > glucagon > adenylyl cyclase >

+
V

phosphorylation < protein kinase A

" V

of glycogen synthase of glycogen phosphorylase

V V

becomes inactive becomes active

+
> glycogenesis > glycogenolysis
 Anabolic state
I/

FED insulin + ↓↓ CAMP

> > phosphodiesterase >

dephosphorylation of <

V v

glycogen synthase glycogen phosphorylase

v v

becomes active becomes inactive

v v

glycogenesis glycogen olysis

Glycogen phosphorylase >

2 forms : a : phosphorylated + active

b : dephosphorylated + inactive

V V

ACTIVATORS : INHIBITORS : -
insulin
'
•

glucagon : only liver

-

glucose : only liver

-
NE ; epi '
GGP ; AIP
'
CAMP dephos.in/lation of
'
FIP : only liver
'
5 AMP only muscle protein phosphatase
glycogen ph.ir/lase
' .
: <

>
i. e allosterically
'
5- AMP directly activates
gly.ph rylase by binding
-
to the enzyme ; NOT by ph.in/lation
in liver ; muscle > CAMP independent activation of glycogen olysis

ca -
calmodulin sensitive phosphorylase kinase

Glycogen storage
Glycogen Storage
diseases
Diseases

TYPE + DISEASE ENZYME SUBS . ACC . ORGAN

GGP
1 : von
gierke's glucose 6 ph tase
-
liver

pompe's acid maltase

11 :
glycogen in lysosomes
liver ;

111 : Cori 's limit debranchingenz .

limit dextrin muscle ;

dextrinosis brain

111 : anderson's branching en } . amylopectin

V : Mcardle 's Muscle ph.ir/lase muscle glycogen muscle

V1 : Her's Hepatic phrylase Liver glycogen liver

 Von Gierke’s Disease
-
MC glycogen storage
in liver
disorder >
corn .
to
glycogen :
hepatomegaly -1
enlarged kidneys

glucose 6 phosphate > glucose

GGP -

Ease

excess

vÉ v

HMP pathway ✓ severe

hypoglycemia
+
pyruvate
v
>
KB > Ketosis

ribose 5- ph . v "

lactate acetyl CoA v

u KETOMC HYPOGLYCEMIA

purines v v FASTING HYPOGLYCEMIA

catabolism lactic acidosis FAS

v causes of HYPER URICEMIA :

uric acid u v
'
lactic acidosis

competes c- TGS '

HMP pathway : ↑ ribose 5- ph .

v uric acid for .

sequestration of Pi +
hyperuricemia excretion v v

^
hyper Taenia PRPP

"

↑↑ purines

seq of Pi
. : phosphate gets locked c- GGP ☒ ATP not formed ADP ; AMP > degrade
Complications of Von Gierke’s

pulm . HTN

hepatic adenoma

pancreatitis

renal failure

:
Polycystic ovaries

Osteopenia
 Pompe’s Disease
only glycogen storage disease which is also a lysosomal storage disease .

Clf : hypertrophic cardiomyopathy > cardiac failure > death

progressive SK .

myopathy 2 years

Px : recombinant enzyme : at glucosidase -

✗ myozyme

Cori’s Disease : Limit Dextrinosis

de
branching enzyme > compound c- ↑↑ ✗ (I >
G) bonds : limit dextrins

NO renal
enlargement NO hyperuricemia
/ V15 gierke 's
'
.
>
Von

'
NO lactic acidosis

Anderson’s Disease : Amylopectinosis

branching enzyme > during glycogenesis very less no ✗ (I >
G) are formed

=
amylopectinoasis < produces amylopectin ( part of starch )

↓↓↓↓ branched than glycogen

 Mc Ardle’s Disease
muscle glycogen ph rylase -

> glycogenolysis :
glucose not formed

i.
diagnostic feature : NORMAL lactate after exercise v

i. NO lactic acid
^^
breakdown for glucose
normally : after exercise lactate levels due to
glycogen

exercise intolerance < "

:
for ATP + pyruvate
absent in Mcardle 's

aerobic glycolysis is

↑↑↑ levels of <

r lactic acid

muscle
glycogen normal lactate levels
'

. .

TYPE I GSD : von gierke's v15 TYPE V1 GSD : her's

v v

severe hypoglycemia mild hypoglycemia

ketosis no ketosis
 HMP
HMPPathway
Paway
HMP : hexose monophosphate >
'
.
'

starting material : GOP

PPP : pentose phosphate pathway >

:
'

ribose 5P is synthesised

FED state >

insulin >
anabolic pathway @ cytoplasm of : liver ; thyroid
adipose
alternate
glucose oxidn pathway lactating glands
-
mammary
-
MAJOR source of NADPH adrenal cortex

other minor sources : -

malic enzyme RBC

cyt . isocitrate dehyd .

gonads
ONLY of RIBOSE 5 PH NEVER in lactating MG
-
source . : non -

'
NO ATP is produced skin

muscle

Oxidative Phase Non-oxidative Phase

NADPH produces ribose 5P
'

produces
'

•
irreversible -
reversible

- -
cells that req . NADPH >> ribose 5P : both oxidative + non oxidative phases
occur

- .
cells that req .
ribose 5P NADPH : ONLY non -
oxidative phase occurs

HMP pathway
Pathways that DO NOT produce ATP
.

>

-
RL shunt
-
uronic acid pathway .
✗ -

oxidation

-
oxidn Of VLCFA
 EMP HMP
:
glycolysis pathway

major glucose pathway minor

glucose pathway

catabolic pathway anabolic pathway

"

CO2 prod

ATP used +
produced NEITHER

location all cells special sites

dehydrogenase : NAD dehydrogenase : NADP

starts c- GGP
glucose

Oxidative Phase
I. NADP NADPH
-
,

GGP >
6 phospho -

gluconate rate limiting enzyme

CHO GGP dehydrogenase COOH +
I 1
C ^
C >
1st committed step
1 I
+
f -
f
C C regulated step
1 I
NADPH c
c
I 1

C -
O -
P C -
O -
P
2 .
NADP NADPH
7

6 phospho gluconate -

>
3 keto 6 phospho -

gluconate
Gph gluconate dehydwg
-
.

COOH COOH
I 1
C C
I 1
•

H - C -
OH > C = 0
I 1
C C
I 1

C C
1 I
C- O -
P C -
O -

3. spontaneous decarboxylation :

-
CO2
,
ribulose 5P
3 keto 6 ph .

gluconate >

COOH →
CO2 C
I 1
C
C =D
I
1
C =D >
C
I
I
C
C
1
I
C
1 C -
O -
P
C -
O -
p

I GGP : 2 NADPH 3 molecules of ribulose 5P enter NON -

OXD .
phase
.

I CO2

is 1 ribulose 5P > 3A

a
 Non-Oxidative Phase
3 molecules of ribulose 5P enter ; no .

of carbons 4 rearrangements

5 ribulose 5P 5 ribulose 5P -
transketolase : 2C transfer
•
trans aldolase : 3C transfer

epimerase isomerase

v v

5 xylulose 5P 5 ribose 5P

-12
131 transketolase ; Mg
v

7 Sedoheptulose 7P + 3 G3P ribulose 5P

transaldolase epimerase
v v

6 FGP + 4 erythrose LIP 5 xylulose 5P

transketolase

v v

6 GGP 6 FGP + 3 G3P

6 GGP
 Function of HMP pathway

Glutathione >
tri peptide : glutamate + cysteine +
glycine

glutamate : COOH cysteine : COOH glycine : COOH

d- MHz { -
MHz {
1 I 1
C C -
SH MHz
,
C •

1 due to
COOH seducing prop .

of glutathione is

RBC :

oxidised

NADPH GSSG 1-120

a- ,

glut .
reductase ; glut peroxidase
. :
scleroprotein
132 "

" t
NADP GSH Hzoz has selenocyskine
reduced @ active site

ENZYME activity MARKER for

transketolase Bs def .

glutathione reductase Bz def .

transaminase 136 def .

 G6PD deficiency
MC enzyme defect ; ✗R

1- >

-
oxidative stress causes hemolysis
-
hemolytic anemia

Heinz bodies + bite cells

-
neonatal jaundice I ad after birth
-

unwnjugated <

bilirubin
↑ ↑ resistance malaria
to falciparum
-

sickle cell trait ; thalassemias

-

Uses of NADPH

V V V V

lipid synthesis cholesterol FA

synth elongation 10450 OH Cation of
-

-
aromatic comp .

-
steroids
-
alcohols

drugs
-
 Uronic
Uronic acid Pathway
acid paway
1 .

GIP > UDP-glucose

UDP glucose

pywph.ir/lase

2.

UDP-glucose >
UDP -

glucuronic acid >

glucuronic
acid

CHO CHO
I 1
C C
1 I
C > c
I
1
C
1 C

C I

1 C
CH OH I
2 ☒
COOH

glucose
glucuronic acid

3. D-
glucuronic acid L
gulonale L ascorbic
- -

> >

CHO * CH OH C- gulono -
lactone acid
2
1 ,
c reduction c oxidase
I 1
C C
1 I v
C C
1 absent inhumans
,
c c
l
1
COOH COOH
 L xylitol
4 L
gulonale xylulose
- -

. > - -- ±
,

'
Xylulose reductase
-

coz

essential pentosuria

5 . Xylitol >
D- ✗ ylulose > xylulose 5P > enters HMP

Xylulose reductase :L ylulose in urine

Essential Pentosuria ✗
-

>

'

benign condition ; d /d- c- DM u

also + benedict's test

-
pentosuria : seen after consumption of
of fruits + trial 's test
large am .
×

( pentose ) < dld glucose

Garrod’s Tetrad
CYSTINURIA : defective di -
basic AA transporter > absorption + reabsorption
of basic AA ; cysteine

ALKAPTONURIA :
homogentisak oxidase

ALBINISM : tyrosinase

PENTOSURIA : ✗ylulose reductase

 Galactose
Galactose
Metabolism
Metabolism
i. occurs @ LIVER only
1. galactose
ATP

galacto kinase
'
ADP v

galactose 1-
IP + UDP -

gluiose : EXCHANGE reaction

§
2-

gal IP uridyl transferase

- -

GALT : RLE

UDP galactose +
glucose IP -

glycolysis glycogen synth

-

> ; .

3.

epimerase
/

UDP glucose > glycogen synthesis

Energetics of Galactose >

-
energetics of glucose

complete breakdown of 1 galactose molecule : releases 32 ATP ( glucose)

-
?⃝
 Galactosemia

Minor-Type > galactokinase

galactose → gal
-
IP

aldose reductase

galactitol dukitol > causes 01L DROP CATARACT

GALT gal IP uridyl transferase

Classical-Type : -

>

IP
ace .

of galactose @ liver ; brain > jaundice ; vomiting

- hepatomegaly
× liver failure
galactokinase seizures ; lethargy ; irritability
MR

galactose galactitol / dukitol : oil drop cataract

-

>

•
↑↑ v10 E. coli infection > NEONATAL SEPSIS

: urine , benedict's test : + ve

Px : breast milk ✗ + lactose

glucose oxidase test : ve free diet till 4- 54 age

-

>

: @ 5y gal IP ph.in/lase
•

:
-

confirmation :
enzyme assay using RBC becomes active
 Lactose synthesis in Mammary glands > @ :
golgi complex

enzyme : lactose synthase > galactosyltransferase

UDP -

galactose +
glucose > gal glu 1312 4)
- → + UDP

=
lactose synthase

lactose

Fructose
Fructose
Metabolism
Metabolism
location : mainly LIVER -
fructose > most LIPOGENIC

sugar
source : sucrose ; monosach .

form fruits ; honey ; sugarcane

fructose entry into cells : insulin independent

ingestion : no insulin response

energy source for sperms

ENERGETICS -
glucose I 32 ATP

ATP ADP
,

fructose FIP DHAP

> >
+
glyceraldehyde
fructo kinase do ATP

hexo kinase kinase

>
qzp ADP
glycolysis < <
 FI Gbp , >
☐ HAP + G3P

aldolase A ; aldolase C

( most tissues ) ( brain)

FIP > DHAP +

glyceraldehyde
aldolase B

Essential (or) Benign Fructosuria

due to : .
fructokinase
-
↑ fructose in blood
'
v
renal threshold

: benedict 's → + ve ( reducing )

seliwanoff 's >

+ ve ( keto )

Hereditary Fructose Intolerance

AR

aldolase B ✗ >
↑↑ FIP -

> hepatic glycogen ph rylase -

✓ v

Pi sequestration : hyperuricemia fructose incl . : hypoglycemia

asymptomatic till weaning off breast milk >

later c- ingestion of fruits c- sucrose

hepatomeg .

; jaundice ; vomiting ; lethargy ; seizures <

+
fructose