PHYSIOLOGY

AJT'o.To.JT'eeh.coln
Table of Contents
Carbohydrate Metabolism 1
Citric Acid Cycle 1
ETC and Oxidative Phosphryation 2
Gluconeogenesis 4
Glycogen Metabolism 6
Glycolysis 9
Pentose Phosphate Pathway 10

Fat & Cholesterol Metabolism 13

Fatty Acid Synthesis 15
Fatty Acid Oxidation 18
Ketone Body Metabolism 21

Nucleic Acid Metabolism 23

Nuclcleotide Metabolism 23

Protein Metabolism 29
Amino Acids and Protein Folding 29
Enzyme Function 31
Amino Acid Metabolism 32
Nitrogen & The Urea Cycle 33
Protein Structure & Synthesis 38
 NOTES

ama CARBOHYDRATE
NOTES
METABOLISM

CITRIC ACID CYCLE

(l(REBS CYCLE)
osms.i"l/ei-lrie-o.eid-e14ele
• Generates energy in the form of GTP, MNEMONIC: T -rex Loves
NADH, and FADH2 and. Cares For Nachos
• Occurs in mitochondria Five required cofactors
• Starts with acetyl-CoA----> C02 Thiamine
Lipoic acid
Process
CoA
• Acetyl-CoA + oxaloacetate (via citrate
FAD•
synthase) ----> citrate + CoA
NAD•
• Citrate (via aconitase) ----> isocitrate
• lsocitrate + NAO- (via isocitrate
dehydrogenase) ----> a-ketoglutarate +
NADH + co2
O Rate-limiting step
• a-ketoglutarate + NAD+ + CoA-SH
(a-ketoglutarate dehydrogenase) ---->
succinyl-CoA + NADH + C02
O Requires five cofactors: thiamine, lipoic
acid, CoA. FAD-. NAO•
O See mnemonic
• Succinyl-CoA + phosphate+ GDP (via T -rex Loves i.
succinate thiokinase) ----> succinate + GTP Gares For Nac;hos
• Succinate + FAD• (via succinate
Figure 1.1 Mnemonic for the five cofactors
dehydrogenase) ----> fumarate + FADH2
required by a-ketoglutarate dehydrogenase.
• Fumarate + H20 (via fumarase) ----> malate
• Malate + NAO• (via malate dehydrogenase)
----> oxaloacetate + NADH
O Oxaloacetate then enters next cycle
• Generates one GTP molecule, three NADH
molecules, one FADH2 molecule

1
 afratafreeh.com exclusive
0

t x Aoet1IC.eA )l~,....c.oA
C.ITRATE
~ 0 Oii O

CITRATE SYNT -o~o- AC.ONITASE:

,o o 3
~?, o'"(o'
O'lALOAC.ETATE ·oyl-1.0•

MALATE
OE:HYDROGE:NASE:
o
t: 0

NADM

NAD·
-o~o- ISOC.ITRATE

NADM
~

NAD• ~SOCITRATE
OE:HYDROGE:NASE:

o
C.O,
o
MALATE _0~o- -o..l.-yllo- o<-kETOGLUTARATf.

FVMARATE HYORASE \H:iO

Ho't. o C.~:~~~.
NADM
~-~ETOGLVTARATE:
OEHYDROGE:NASE

0 0 ~

F'UMARATf. -o~o-FADM ~p~b~+

-o..ll_y5-c.oA 5UGC.INYL-GeA
o~a GTP o
FAD'o C.oA-~
SVC.CINATE OE:HYOROGENASE -o~o- SVC.C.INATE THIO~INASE

0
SUGGINATE

S NADM ) "I ATP

t CITRIC. AC.ID C.YC.lE t FADHa-- ...
) ~ ATP~ 1~ ATP
tGTP tATPT

Figure 1.2 The citric acid (Krebs) cycle. Each acetyl-CoA molecule generates 12 ATP.

ELECTRON TRANSPORT CHAIN &

OXIDATIVE PHOSPHORYLATION
osms.i"l/e-le-C1nd-oxidC1-live-phosphor14 IC1-lion
Oxidative phosphorylation
• Generates energy as ATP
• Occurs in inner mitochondrial
Electron transport chain
• Series of proteins, lipids, metals that
facilitates electron movement - proton
gradient used to create ATP
• Starts with electron donors NADH, FADH2
O NADH from cytoplasm comes through
malate-aspartate shuttle
, FADH2 from cytoplasm comes through
glycerol-3-phosphate shuttle
membrane , NADH donates electron to complex I
(contains flavin mononucleotide, iron-
sulfur centers) - NAO·
, FADH2 donates electron to complex II
(i.e. succinate dehydrogenase) - FAD
, Electrons from either complex flow into
coenzyme Q (ubiquinone)
, Coenzyme Q passes electrons to
cytochromes (proteins with heme
2
 groups - Fe3- + e· ...... Fe2-J: complex Ill
(cytochromes b and cl) -> cytochrome
c-> complex IV (cytochrome oxidase:
cytochromes a, a3) -> oxygen
• Movement of electrons=- electrical current
-> complexes I, Ill, IV use this energy to
pump protons across inner mitochondrial
membrane
• Protons can move back into mitochondria
through F O-> proton gradient forms,
powering F1: ADP-> ATP
n Collectively called complex V
• An ADP/ATP antiport pumps ATP into
cytoplasm of the cell, supplies complex V
with new ADP

G'ITOGHROM£ S

C.OMPLEX I

.!..o
.2 a +2W~HO .l

Figure 1.3 The flow of electrons through the electron transport chain, which takes place in the
inner mitochondrial membrane.

3
 CELL CYTOPLASM
APP/ATP
ANTI PORT

INNER MITOCHONORIAL
MEMBRANE
MITOCHONDRIAL MATRIX

Figure 1.4 Oxidative phosphorylation. The passing of electrons along the electron transport
chain generates an electrical current, which provides the energy that allows complexes I, Ill, and
IV to pump protons into the space between the inner and outer mitochondrial membranes. This
creates a gradient across the inner mitochondrial membrane. The protons use proton channel Fa
to flow down the gradient, back into the mitochondrial matrix. Fa is attached to enzyme F1• an
ATP synthase, which uses the proton gradient to phosphorylate ADP - ATP.

GLUCONEOGENESIS
osmsJl/glueoneogenesis
• Synthesis of glucose from non- pyruvate
carbohydrate substrates • Obtaining ATP, glycerol
O E.g. amino acids, lactate, glycerol , Triacylglyceride breakdown - fatty
• Occurs primarily in liver cells; also in acids and glycerol - acetyl CoA + ATP
epithelial cells of kidney, intestine (~-oxidation)
O Inside cytoplasm, mitochondria, • Pyruvate (via pyruvate carboxylase) -
endoplasmic reticulum oxaloacetate
• Starts with glycogenolysis after glucose • Oxaloacetate (malate dehydrogenase) -
depletion ma late
• Malate leaves mitochondria; malate (via
Process
malate dehydrogenase) - oxaloacetate
• Like backwards glycolysis, with three
• Oxaloacetate (via PEPCK) -
exceptions
phosphoenolpyruvate (PEP)
• Obtaining pyruvate
• PEP undergoes reversed glycolysis
O Lactate (via lactate dehydrogenase) - reactions until dihydroacetone-phosphate
pyruvate (DHAP)
O Amino acids (not leucine, lysine); e.g. , Alternatively, glycerol (via glycerol
alanine (via alanine transaminase) - kinase) - glycerol-3-phosphate;

4
 afratafreeh.com exclusive
glycerol-3-phosphate (via glycerol-3- • Fructose-6-phosphate (via isomerase) --->
phosphate dehydrogenase) ---> DHAP glucose-6-phosphate
• DHAP (via aldolase) ---> fructose-1,6- • Glucose-6-phosphate (via glucose-6-
bisphosphate phosphatase) ---> glucose
• Fructose-1.6-bisphosphatase ---> fructose-
6-phosphate
O Rate-limiting step

START

-oyl ·oPo· -o r
fl
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&LVUROL·3-PHOSPHATE. FRVC.TOSE.·I,,. FRVC.TOSE.-,.
(C.3P) BISPHOSPHATE (Mr&4.1111TIN"5TU) PHOSPHATE

mmmmmmmmmmmmmmmmmmnnmmnmmnmmmmnmmn~
;~
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ON
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PHOSPHAT£

Figure 1.5 The process of gluconeogenesis.

5
 GLYCOGEN METABOLISM
osms.i"l/gl14eogen-me-lo.\>olism
• Polymer of glucose molecules linked by
glycosidic bonds
• Stores energy in skeletal muscle, liver
Glycogen synthesis
• Glucose + phosphate (via hexokinase)
glucose-6 phosphate
• Glucose-6 phosphate (via
phosphoglucomutase) - glucose-1-
phosphate + energy (UTP)
• Glucose-1-phosphate + UTP (via UDP-
glucose pyrophosphorylase) - UDP-
glucose
• UDP-glucose added (via glycogen
synthase) to glycogen branch/glycogenin
(- alpha-1,4-glycosidic bond)
• Branching enzyme cuts off part of glucose
chain, creates branch (- alpha-1,6-
glycosidic bond)
Glycogen breakdown, AKA glycogenolysis
• Glucagon - liver breakdown of glycogen
• Epinephrine - skeletal muscle breakdown
of glycogen
• Glycogen phosphorylase cleaves alpha-1,4
bonds on branches; catalyzes phosphate
transfer to glucose residue - one glucose-
1-phosphate is released at a time
o Repeats until branch is only 4 glucose
units long
• Debranching enzyme: 4-alpha-
glucanotransferase moves 3 glucose units
off branch, onto main chain; alpha-1,6-
glucosidase cleaves last remaining glucose
• Cleaved glucose-1-phosphate (via
phosphoglucomutase) - glucose-6-
phosphate
, With glucose-6-phosphate
• In liver cells, glucose-6-phosphatase
- removes phosphate - free glucose into
blood
• In skeletal muscle, glucose-6-phosphate -
glycolysis pathway
Regulation
• Principles
, Glycogen synthase: active without
phosphate
, Glycogen phosphorylase: active with
phosphate
• Hormones
, Insulin: binds to membrane tyrosine
kinase receptors - protein phosphatase
removes phosphates - glycogen
synthase activates, glycogen
phosphorylase deactivates
, Glucagon: binds to membrane G-protein
coupled receptors (in liver) - ATP
(adenylyl cyclase) - cAMP - kinase
A - adds phosphates - glycogen
phosphorylase activates, glycogen
synthase deactivates
6
 GLYCOGEN SYNTHESIS
STEP to. o·
I
0--P=O
I
0
'CjH,.
HEXOKINASE H .h-,~ PHOSPHOGLUCOMUTASE
I 'I!
1/H
~.....~
Ho ~-~
~..... ,
OH
H OH

GLUCOSE GLUCOSE-, PHOSPHATE GLUCOSE-tPHOSPHATE

STEP 111
Ho,% ~00
~ll co INH

H
I
.h-o'-.~ UDP-GLUCOSE o-,-o-f-o'l.-,o....J'A:o
•/H I 't PYROPHOSPHORYLASE OH OH '\--(
f,~c-~ ~ ..... o-P=o·
Ho
,?
I I t
H OH er OH OH

GLUCOSE-tPHOSPHATE UTP UDP-GLUCOSE

STEP~
en& of GLYCOGEN BRANCH/
NEW LINEAR GLYCOGEN MOLECULE

~ll
~1 # co
I 0 NH
GLYCOGEN SYNTHASE/
GLYCOGENIN
0 .•
_
i" o-~-o-f-O).,..o~~o 0 .
OH OH '\--(
\._ ALPHA-1,4-GLYCOSIDIC BOND
OH OH
+ 0
UDP-GLUCOSE
a a
O-f-O-~-o
{NH
l!..N~o
~ ~~
OH OH
UDP
STEP~

ALPHA 1,,
GLYCOSIDIC BOND ) 1,,;;>,<;~~>C>-c>-0

~~"""--'~

BRANCHED GLYCOGEN TREE

Figure 1.6 The process of glycogen synthesis.

7
 GLYCOGEN BREAICDOWN
STEPt
GLYCOGEN
PHOSPHORYLASE
+
BRANCHED GLYCOGEN <DiR
O-P-0-
~RO-P-0- ~RO-P-0-
I I I
o- o· o·
GLUCOSE-1PHOSPHATE
STEP ao.
DE8RANCHING ENZYME:
4-alpha-glucanohansferase

STEP a1,

' DE!rANCHING ENZYME:

~pho-t,,-91,u-.•~ (S) GLUCOSE

STEP~
0
II
o·-P-o·
I
C::,fl phosphoglucomutase 0
O-P-0-
1
o-
GLUCOSE-1PHOSPHATE
b
GLUCOSE-, PHOSPHATE

llVER MUSCLES
0
II
o·-p-o· NO <aLUCOSE-,-PHOSPHATAS£
I
0 * USES G.LUC.OSE.-,-PHOSPHATE
4 GaLVC.OLVSIS PATH\..IAV
b
GLUCOSE-, PHOSPHATE
~MAKES EIIIE.P.Ga'i

1
GLUCOSE-,-
PHOSPHATASE
C)

Figure 1.7 Glycogen breakdown. The process is completed differently in the liver and skeletal
muscles due to the respective presence and absence of glucose-6-phosphatase in each.

8
REGULATION REGULATION
~.INSULIN \ a. GLUCAGON

'-TVROSINE KINAS€ '-<::.-PROTEIN

REC.£PTOi C.OUPL£D RECEPTOR

i l

___
ADENVL'i'L C.VC.LASE
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l
iEMOVE.S;.._PHOSPHATES _ 4ATP-~AMP
.r:'
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GL'i'C.O&EN &LVC.OGiEN
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SYNTHASE PHOSPHOiYLASE
____ _
ADDS PHOSPHATE.S
;.._
.(" ~
GL'i'C.O&EN &LVC.O&EN
MAK£S AC.TIVE MAKES INAC.TIV£ SYNTHASE PHOSPHOiYLASE
t G.L'iGOGEN i G.L'i'C,OGEN
S'i'NTHE.SIS BREAKDOWN

~
MAKES INAC.TIV£ MAKES AC.TIVE
i SYNTHESIS f BREAKDOWN
Figure 1.8 The role of insulin in the regulation Figure 1.9 The role of glucagon in the
of glycogen levels. regulation of glycogen levels.

GLYCOLYSIS
osms.i"l/gl14eoh4sis
• Energy-producing breakdown of glucose glucose-6-phosphate
into pyruvate , Uses one ATP molecule
• Occurs in cytoplasm of all cells • Glucose-6-phosphate (via
phosphoglucoisomerase) - fructose-6-
PROCESS phosphate
• Fructose-6-phosphate (via
• Glucose transporter (GLUT) carries glucose
into cell phosphofructokinase-1) - fructose-1,6-
bisphosphate
• Kinases {hexokinase, glucokinase)
, Rate-limiting step
phosphorylate glucose - conformational
change, i.e. glucose can't diffuse out) - , Uses one ATP molecule

9
 afratafreeh.com exclusive
Enzyme activation • 3-phosphoglycerate (via mutase) -
• Fructose-6-phosphate (via 2-phosphoglycerate (x2)
phosphofructokinase-2) - fructose-2,6- • 2-phosphoglycerate (via enolase) -
bisphosphate phosphoenolpyruvate (PEP) + Hp (x2)
O Up-regulated by insulin; down- • PEP + ADP (via pyruvate kinase) -
regulated by glucagon pyruvate + ATP (x2)
° Fructose- 2,6-bisphosphate activates , Creates two ATP molecules
phosphofructokinase-1 , Up-regulated by fructose-1,6-
• Fructose-1.6-bisphosphate (via aldolase) bisphosphate (feed-forward regulation)
- glyceraldehyde 3-phosphate (G3P) + , Down-regulated by ATP, alanine
dihydroacetone-phosphate (DHAP) • In total, process generates two ATP
O
DHAP (via isomerase) - G3P - 2x molecules
G3P molecules per glucose • In cells with oxygen, pyruvate enters citric
• G3P (via G3P-dehydrogenase) - acid cycle, electron transport chain to make
1,3-diphosphoglycerate (1,3-BPG); H· + more ATP
NAD· - NADH (x2) , 30-32 in total
0 2x NADH enter electron transport chain
• 1,3-BPG + ADP (via phosphoglycerate
kinase) - 3-phosphoglycerate + ATP (x2)
° Creates two ATP molecules

PENTOSE PHOSPHATE PATHWAY

osms.i"l/pen-lose-phospho.-le-po.-lhwo.14
• Synthesis of ribose, NADPH from unused Reversible non-oxidative phase
glucose • Two options:
• Occurs in cytoplasm of all cells , Ribulose-5-phosphate (via isomerase)
- ribose-5-phosphate
Irreversible oxidative phase
, Ribulose-5-phosphate (via epimerase)
• Glucose-6-phosphate + NADP· (via
- xylulose-5-phosphate
glucose-6-phosphate dehydrogenase) -
6-phosphogluconate + NADPH
O Rate-limiting step
• 6-phosphogluconate + NADP-
(6-phosphogluconate dehydrogenase) -
ribulose-5-phosphate + NADPH + C02

10
 a ENERGY (ATP) TRAC.KER

r
• •
_____ . ,., _Q,. GLUCOSE

•~HEXOKINASE.
GLUC.OKINASE

G J,~ATP II
INSULIN -o)-o_: APP
...~ GLUCOSE G-PHOSPHATE
uLUCAC.ON ~'
,CARBON _;) - l , lI ...
PHOSPHOG.LUC.OISOMERASE

FRUC.TOS£ 2.,-BISPHOSPHATe:'1---? '-""o

G-·-vo.f PfK2 G-•-yo~
~.., . . FRUCTOSE G-PHOSPHATE

. . \+___ 1
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le: ATP
APP
8
U
G-. ...
~-G FRUCTOSE t.G-81SPHOSPHATE
...
ALPot.AS£ lr O
(G3P) MO (CHAP)
~'@
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xl--- (G3P) 0~'@

1 ~ ISOMERASE

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(1.3-BPG.)
1,3-BISPHOSPHOC.LVCERATE)(.~ u T'1~.»'G
o_
+ NAPH )(.2 -----. ELECTRON TRANSPORT CHAIN

a 2x APP'
2xATP~.
Ho_ _l
IT
p
PHOSPHOGLYCERATE KINASE

T ~ 'Gl-PHOSPHOGrl.Yc..£RAT£ x.2
ll MUTASE

Ho~H 2-PHOSPHOGLVC.ERATE x.2

0

Figure 1.10 Glycolysis.

11
 r
• •

Ho
GLUCOSE
OH

G:t GLUCOSE
,-PHOSPHATE

GLUCOSE-,-PHOSPHATE ~ NADP+
DEHYDROGENASE(G,PD) ~NADPH

MO_
OM OM
J.. J.. ,....,. '
G
lf TT ·o'
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Olf
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o Qlf

~
OM
'G
OM OM
RIBOSE-5-PHOSPHATE XYLULOSE-5-PHOSPHATE

Figure 1.11 Pentose phosphate pathway.

12

CHOLESTEROL METABOLISM
osmsJl/ eholes-leTol-me-lo.\>olism
• Cholesterol insoluble in water ----> moves
through blood stream with lipoproteins
• Cholesterol used in cell membrane for
flexibility, durability
O At I temperature, cholesterol squeezed
between phospholipid molecules, keeps
membrane fluid
O At t temperature, cholesterol pulls
phospholipid molecules together
• Cholesterol used by adrenal glands,
gonads; makes steroid hormones
O Adrenal glands form corticosteroids
(e.g. cortisol, aldosterone); testes
(testosterone); ovaries (estradiol,
progesterone)
CHOLESTEROL SYNTHESIS
• Mevalonate pathway; occurs in smooth
endoplasmic reticulum
Pathway
• Two acetyl-CoA molecules joined by
acetyl-CoA acvltransferase e- acetoacetyl-
CoA, CoA
• HMG-CoA synthase combines acetoacetyl-
CoA, acetyl-CoA----> 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA), CoA
• HMG-CoA reductase reduces HMG-CoA
into mevalonate, removes CoA-SH, water
O Rate limiting cholesterol synthesis step
• Mevalonate-5-kinase uses ATP to
phosphorylate mevalonate----> mevalonate-
5-phosphate
• Phosphomevalonate kinase uses ATP to
phosphorylate mevalonate-5-phosphate ---->
mevalonate pyrophosphate
• Mevalonate pyrophosphate decarboxylase
removes carboxyl group----> isopentenyl
pyrophosphate
NOTES
• Geranyl transferase condenses three
isopentenyl pyrophosphate molecules ---->
farnesyl pyrophosphate
• Squalene synthase condenses two farnesyl
pyrophosphate molecules ----> squalene
• Oxidosqualene cyclase converts squalene
into lanosterol (cyclization)
• Lanosterol converted into
7-dehydrocholesterol, eventually
cholesterol
Cholesterol synthesis regulation
• SREBP, INSIGl, SCAP (collection of
proteins)
, ! cholesterol ----> INSIG 1 falls off of
SCAP-SREBP----> SREBP cleaving ---->
binds sterol regulatory element----> l
HMG-CoA reductase gene expression
CHOLESTEROL USE & STORAGE
• Majority of cholesterol used by liver, ends
up as bile acids
• Include cholic acids, chenodeoxycholic
acids
, Conjugation with taurine forms
taurocholic acid, taurochenodeoxycholic
acid respectively
, Conjugation with glycine forms
glycocholic acid, glycochenodeoxycholic
acid respectively
• Stored in gallbladder
• Released into intestines after meals, aids
fat digestion
• Most reabsorbed by intestine; some
eliminated through feces
, Enterohepatic circulation: reabsorbed
bile acids enter portal bloodstream,
return to liver cells
13
 CHOLESTEROL S'lNTHESIS ME. VALONATE PATHWAV
AC€TVL-C.A
AC.£TOAC€TYL-C..A
0
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s
A C,H, AC.ETVL-C.A AC.VL-
TRANSF£RASE. 11,~MSC..A
+
0 +
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s C,H,
CoA

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-o~ ~SCoA
C.,A-SH i. H,O
ME. VALONATE. HMG, C.oA
ATP
M£VALONAT£-
S-Klt-lAS£

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\ )
PHOSPHOME. VALONATE
KJNAS£ ME VALONATE PYROPHOSPHATE

ME.VALONATE
PVP.OPHOSPHATE.
DEC.ARBOXVLASE. TP

r CH3 C,~ C,~

~C,~C,Ha.0-0,v~J.l
:l GrERAN'<'L
(RANSf£RASE.

FARN£SVL PVROPHOSPHATE
SGUALENE.
S'<'NTHA!,£

I
OXIDOSQUAL£NE.
C.'<'C.LAS£
)
~ C,H3
C,~ •o
SQUAL€NE. "" CM,
LANOST€P.OL
GVGLIZATIOM

!
MO
<
C.HOLESTE.ROL 7-D€HVDROC.HOL€STEP.OL

Figure 2.1 Cholesterol synthesis via the mevalonate pathway.

14
 CHOLESTEROL S'iNTH€SIS l'E.GULATION
!CHOLESTEROLLEVELS
SPEEDS UP UID06ENOUS
C.HOLESTEROLS'#NTHESIS

t
t HMGi-C.oA P.EDUC,TASE
INSl(;a 1 SC.AP

-1 () /°D.. i
., ?----.-\__ t-
/ STEROL Hl'IG,-C,A
REGULATORY REOUCTAS£
EL£1'1£NT (.ENE

-
Figure 2.2 Cholesterol synthesis regulation.

FATTY ACID SYNTHESIS

osms.i-l/f o.tl14-o.eid-s14n-lhesis
• Fatty acids: simplest lipid form
O Long carbon, hydrogen chain atoms
O Classification: short, medium, long, very
long chain fatty acids
• Short, medium chain fatty acids
O Primarily obtained from diet
• Long, very long chain fatty acids
O Synthesized by liver, fat cells
• Synthesis: combine acetyl-CoA molecules
into palmitoyl-CoA
0 16 carbon chain fatty acid; precursor to
longer chain fatty acids
BEFORE FATTY ACID SYNTHESIS
• Acetyl-CoA must be obtained
• In response to insulin, cells take in glucose
° Consumed as carbohydrates
• In cell, glycolysis breaks glucose down into
pyruvate molecules
• Mitochondria convert pyruvate into acetyl-
CoA using pyruvate dehydrogenase
• Typically, acetyl-CoA combines with
oxaloacetate, enters citric acid cycle -
forms citrate - forms electron carriers
(join electron transport chain in oxidative
phosphorylation) - creates adenosine
triphosphate (ATP)
FATTY ACID SYNTHESIS
• ATP inhibits enzymes needed for citric acid
cycle
, Allows additional acetyl-CoA to be
funneled toward pathways involving
fatty acid synthesis
Stages
• Acetyl-CoA combines with oxaloacetate
- forms citrate - crosses mitochondrial
membrane into cytoplasm
• In cytoplasm, citrate lyase cleaves citrate
into acetyl-CoA. oxaloacetate
, Malic enzyme converts oxaloacetate
into pyruvate (NADP· - NADPH in
process). which can cross back into
membrane
, Then converted back into oxaloacetate
by pyruvate carboxylase
• Acetyl-CoA carboxylase adds carboxyl
group to acetyl-CoA - forms malonyl-CoA
, Rate limiting fatty acid synthesis step
, Requires ATP. biotin, carbon dioxide (A-

15
 B-C) as cofactors
O Acetyl-CoA carboxylase: tightly
regulated (hormonal, allosteric
regulation); hormonal regulation
uses insulin, glucagon to remove/
add phosphate group on acetyl-CoA
carboxylase; insulin I activity/vice versa;
allosteric regulation uses citrate, fatty
acids to ti! acetyl-CoA carboxylase
activity by allosteric binding
• Multiple enzymes form fatty acid synthase
complex (acyl carrier protein (ACP) on one
end, cysteine amino acid on other)
• Acetyl-CoA ACP transacylase removes
CoA group from acetyl-CoA, attaching
resulting acetate to ACP - moves to
cysteine residue
• Malonyl-CoA ACP transacylase removes
CoA group from malonyl-CoA, attaching
resulting malonate to ACP
• 3-ketoacyl-ACP synthase cuts off
carbon (was added to malonate earlier),
released as C02 (leaving behind acetate)
- condenses it with acetate on cysteine
residue - forms four carbon chain (using
one NADPH molecule for each process)
• Malonyl-CoA added across seven cycles
forming 16 carbon chain fatty acid polymer
, Each cycle uses one acetyl-CoA
(converted into malonyl-CoA), two
NADPH molecules
• In total, eight acetyl-CoA molecules
(including initial molecule) used along with
14 NADPH molecules

GLY GOL'ISIS GITRIG AGID GY GL£

0 0

00- AGET'/L-CoA As-eoA

0
2PVRUVATE -\- 0 0

1
HO 0~o-

GiLUC,OSE
OH

ATP
1
OXALOAC.ETATE
0

'~ATP~ ;YC,C.111TRAT£
~oyo-~
. y
CYTOPLASM
-· ..
•

• ETC
o~o-
OH

MITOCHONDRIA

Figure 2.3 Acetyl-CoA is produced by mitochondria using pyruvate molecules (made during
glycolysis). ATP inhibits citric acid cycle enzymes so that acetyl-CoA can be used in fatty acid
synthesis pathways.

16
 MITOCHONDRIA 0/TOPLASM
GITawt...-r SHUTTLE ll0YQ
o~o
AGET'lL-C.oA _ ) GITRAT£ 00

OXALOtC.ETATE - . [c.lTRATE LW\SC

l
GITRAT£ -"
II -», J~
O><.ALOAC.ETATE
~~A

AGET'lL-C.oA
NADP·
O><.ALOAC.ETATE
MALIG E.NZYM£
NADPH
PYRVVAT£1
GARBOXYLAS£ \
PVRUVATE f ____ PVRUVAT 00
0

Figure 2.4 The citrate shuttle transports acetyl-CoA out of the mitochondria by combining
it with oxaloacetate to form citrate. Once citrate is in the cytoplasm, it is converted back to
oxaloacetate and acetyl-CoA, allowing acetyl-CoA to be used in fatty acid synthesis.

AC.ET't'L-C.•A
G£TV L-GoA AGP llATE-LIMITl"'CiiSTEP
TRANSACVLAS£
}.C.ETATE• • ·-_) 0 AG£TVL-GoA 0 0
GARBOX\I LAS£
C.oA ac As-eoA T> HOM-CoA
AC,ETVL-C.oA HC.03
ASC.: ATP. SIOTIN.C.02
Po\ALONVL-CoA
.
.. ,,'
FATTY AGID SYNTHASE. ..... ·•·······
COMPLf.X
v;, ··"'·
I ACETATE
ac MALONVL-GoA A~P
TRANSAGVLAS£
MALONVL-CoA

MALONATE ACETATE
JC, ac
__ ,.) C.,A

NADPH ~
3-K.ETOACVL-~AP
$VNTHA$€
NADP' C.02

AC.E TATE··.·) ACETATE

~TOAGVL-ACP 2c. ac
SYNTHASE

NADP- ' NADPH~

Figure 2.5 Fatty acid synthesis. Malonyl-CoA added across seven cycles---'> 16 carbon chain
fatty acid polymer called palmitoyl-CoA.
17
 FATTY ACID OXIDATION
osms.i-l/f o.tl14-o.eid-oxido.-lion
• AKA 13-oxidation
• Fatty acids broken down to produce energy
• Takes place in mitochondria of heart,
skeletal muscles, liver cells
OXIDATION PREPARATION
• Triglycerides (three fatty acids attached to
glycerol) in adipocytes - broken down by
hormone sensitive lipase
0
Iblood glucose - j glucagon - i
hormone sensitive lipase - j fatty acid
breakdown
• Fatty acids leave fat cells - enter
bloodstream
• Albumin in blood binds to fatty acids -
carries them to target cells
• Fatty acid dissociates from albumin
diffuses into cell
• Fatty acyl-CoA synthetase adds CoA to
end of fatty acid (- fatty acyl-CoA). using
up two ATP molecules
• Fatty acyl-CoA cannot cross cell
membrane, carnitine shuttle used
° Carnitine acyltransferase 1 (outer
membrane) replaces CoA on fatty acid
with carnitine (- fatty acyl-carnitine)
° Fatty acyl-carnitine, CoA cross inner
mitochondrial membrane
° Carnitine acyltransferase 2 (inner
membrane) replaces carnitine on fatty
acid with CoA (- fatty acyl-CoA)
OXIDATION PROCESS
• Occurs on a.13 carbon atoms of fatty acyl-
CoA
O Acyl-CoA dehydrogenase moves one
hydrogen from each carbon to nearby
flavin adenine dinucleotide molecule
(FAD) - FADH2, enoyl-CoA
O Enoyl-CoA hydratase transfers hydroxyl
group to 13 carbon - 13-hydroxyacyl-
CoA
013-hydroxyacyl-CoA dehydrogenase
removes two hydrogens from 13 carbon
transferring one to nicotinamide
adenine dinucleotide (NAO) - NADH,
13-ketoacyl-CoA
, 13-ketothiolase cleaves off two carbon
atoms - acetyl-CoA, fatty acyl-CoA
molecule (two carbons shorter-which
can be further oxidized)
OXIDATION C,YCLE
• One oxidation cycle: 1 NADH, 1 FADH2, 1
acetyl-CoA
• Fatty acids with even number of carbon
atoms
, Oxidation repeats until just acetyl-CoA
remains
• Fatty acids with odd number of carbon
- atoms
, Oxidation repeats until three carbon
propionyl-CoA is left; propionyl-CoA is
broken down differently
• Propionyl-CoA carboxylase
, Adds carboxyl group to propionyl-CoA
- methylmalonyl-CoA
, Cofactors required: ATP. biotin, carbon
dioxide (A-B-C)
• Methylmalonyl-CoA mutase
, Rearranges carbon atoms on
methvlrnalonvl-Co.c.--e succinyl-CoA
, Cofactor required: Vitamin 812
• Succinyl-CoA
, Can enter citric acid cycle/used for heme
synthesis
• Very long fatty acids (22 carbons atom/
longer)
, Peroxisomes may be needed
, Peroxisomal oxidation uses different
enzymes until fatty acid is smaller than
22 carbon atoms
• NADH, FADH2
, Can enter electron transport chain
, Creates ATP - approximately three+
two ATP molecules
18
• Acetyl-CoA
° Can enter citric acid cycle
° Creates more NADH, FADH2 -
approximate total of 12 ATP molecules

BLOOD uLUC.05£ ! ADIPOOITE

1 TRIGLVC,£RID£

~ §~
uLUCAGON ~~
\ I
HORMON£ ~ ~LOODS1REAM
~S£NSITIV£ ~ .-------('t?
LIPAS£ l,-ce~ ~ALBUMIN

~~~
TAP.G.£T G£LLS
~ ~

C..YTOPLASM FATTVACID

~™' c.2ATP

FATW AO/ L-C.oA

S'INTH£TAS£ 2 ADP
u.0
~-CoA
FATT'/ AC.'/L-C.oA

CARNITINE SHUTTLE

FATT'/ AC.'/L-C.oA
0
A --.-------
R(S~~;I O 4:)G:;;•
O C.oA .....
R A S-CARNITINE
... ...
... ... ... ... C.,A A0
FATT'/ AC.'/L-C.ARIIIITIN£ - " •
--- "' "' • ... •
• • •
:'?
• • • .-,
R S-C..ARN1T1NE

MITOCHONDRIAL MATRIX

Figure 2.6 Oxidation preparation requires the use of two ATP molecules and results in fatty
acyl-CoA being present in the mitochondrial matrix.

19
 afratafreeh.com exclusive

H ~ -OXIDATION
~l H i FATTY AC.ID t NADH
R/1"-t~S-CoA 1 FADH2
H I 1 AG£ T'l'L-GoA
H 1" OXIDATION STEP
FAD
AO( l-CoA DEW{ DMG£NAS£
---- FADH2 o,H H i
O H10 R/~"-t~S-CoA
R/CH1~cAS-CoA ~ R
I £NOi{ L-CoA
H £NO'iL-C:.oA H't'DRATAS£ ~ -H'l'DROX'iAC:.'iL-C:.oA
NAO·
0
II
(,.
13C/ "-coA
FATT't' AC.ID CHAIN

H-C
~A S-CoA
R AC,ET'iL-C:.oA
Figure 2.7 Oxidation preparation requires the use of two ATP molecules and results in fatty acyl-
CoA being present in the mitochondrial matrix.

OXIDATION
13C FATTV ACID --- .....) PROPION'/L-CoA
0

~ GITRIG AGID ~S-CoA

~ ~GYGL.t
-OOC S-CoA~ PROPIONY L-CoA
SUC,C.INVL-CoA HEME GARBOXVLASE.
la)TP
METHVLMALONV~ 0 (EI]IOTIN
MUTAS£ -ooc, Jl (go2
1 'S-CoA
VITAMIN 812 M£TH'/LMALONVL-C.oA
Figure 2.8 Fatty acid oxidation when the fatty acid has an odd number of carbon atoms.

20
 l(ETONE BODY METABOLISM
osms.i-l/lce-lone-\,od14-me-lo.\,olism
KETONE BODIES
• Acetoacetate, 13-hydroxybutyrate, acetone
(all contain ketone C=O group)
• Produced by liver mitochondria using
acetyl-CoA
O During physiological states such as
fasting, carbohydrate-restrictive diets
(e.g Atkins, ketogenic diet), intense
exercise, pathological states such as
Type 1 diabetes mellitus, alcoholism
(lack of glucose to power cells)
• Released into bloodstream - picked up
by majority of cells - re-converted into
acetyl-CoA - enter mitochondria, produce
ATP
KETONE BODY BREAKDOWN
• 13-hydroxybutyrate, acetoacetate in blood
diffuses into peripheral tissue mitochondria
, 13-hydroxybutyrate dehydrogenase
converts 13-hyd roxybutyrate back into
acetoacetate
• Thiophorase can add CoA from succinyl-
CoA to acetoacetate - form acetoacetyl-
CoA, succinate
• 13-ketothiolase cleaves acetoacetyl-
CoA with CoA- forms two acetyl-CoA
molecules
, Can enter citric acid cycle to make ATP

KETONE BODY SYNTHESIS

• Two acetyl-CoA molecules are joined
(acetyl-CoA acyltransferase) -
acetoacetyl-CoA + CoA
• HMG-CoA synthase
OAcetoacetyl-CoA + acetyl-CoA -
3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) + CoA (rate-limiting ketone
body synthesis step)
• HMG-CoA lyase removes acetyl-CoA from
HMG-CoA - acetoacetate
• Remaining ketone bodies formed
013-hydroxybutyrate dehydrogenase adds
hydrogen from NADPH to acetoacetate
- 13-hydroxybutyrate
O Acetoacetate in blood spontaneously
loses a carbon - acetone (exhaled
through lungs)

21
 ACET'/L-CoA
Go A
0
As-CoA ACE. TOACE.T'c'L-C,oA
0 0
(Ac-CoA) AC,ET'iL-CoA
0 .,, AOIL- TRANSFERAS£ ~S-CoA
As-CoA
Ac-GoA

HMC:a-C.oA S'INTHASE
L IV\T£-LIMITING STEP

Go A
HMGi-CoA

--
HMGi-CoA
LYAS£ ~
Ac;-GoA HO ~ S-CoA

£ 0 1
A0 AC.ETON£
0
O O t•• k£TON£ BODV )_)l_0_~
AJl 0. ACE rosce TATE ____.;:;, sLooo s•' k£ TON£ BODV

NADH
2•' k£TON£ BODY
------; ~-HVDI\OXVBUT\IRATE.
~-HVD~OXVBUTYRATE. OH O
D£HVDRO&ENASE
NAD·
AJlo-
Figure 2.9 Ketone body synthesis.

CITRIC ACID 0 MITOCHONDRIA of

PERIPHERAL TISSUES
C,VGL£ O As-CoA
OH O A AC.ET'i'L-C.oA
)__)l__o_ S-CoA
P-HVDROXVBUTVRATE /3-IC.£.TOTHIOLASE
AC.ETOAC.E T'i'L-C.,A
I O
NAD· -.\.
yo·ro·
SUC.C.INATE
~-HVDROX'iBVT'iRATE
DEHVDROC:aENASE 0 0 THIOPHORASE
)l)lo_ 0
NADH AC.E TOAC.E TATE o, /'- 1
l . . ,. "S-CoA
O SUC.C.IN'iL-C.oA

Figure 2.10 Ketone body breakdown.

22
 NOTES

ama NOTES
NUCLEIC ACID METABOLISM

NUCLEOTIDE METABOLISM
osmsJl/ nueleo-l:ide-me-1:o.\>olism
Nucleotides • RNA nucleosides (resulting nucleotide)
• Building blocks of DNA, RNA , Adenine + ribose = adenosine
• Consist of 5 carbon sugar, phosphate (monophosphate - AMP)
group, nitrogenous base/nucleobase , Guanine+ ribose = guanosine
0 5 carbon sugar: deoxyribose (- DNA) (monophosphate - GMP)
or ribose (- RNA) , Cytosine + ribose = cytidine
O Nucleobase: pyrimidine (cytosine, (monophosphate - CMP)
thymine for DNA, uracil for RNA) or , Uracil + ribose = uridine
purine (adenine, guanine) (monophosphate - UMP)
O Sugar+ nucleobase = nucleoside

NUCLEOTIDES
PURINES
\"'•
... c.,c......,~
I II p<
o-l-o-~e,NUCLE08ASE
PHOSPHAT£ we..,. H "''•'
M
&ROUP II ,. o ADE.NINE. GUANINE.
O H H P'illMU>INES
H H
OH OH
f· 0
II
0
II
HN,...c.,c.H
N-.,.c.,C.I HN/C.,C..,..C.H,
I II I U I II
o?c.,N,...C.H o?c.,N,...C.H o?c.,N,...c.H
5 CARBON SU&AR M H H

_l_
C.VTOSINE THVl'\INE. URAC.IL

*' DE.OX"'
VP.180SE ~ RIBOSE
w
HOCMQ0 OH H<lCQH,
0 OH
M M H
H M H H

OH H OH OH

-+DNA -+RNA

Figure 3.1 Nucleotide components: a phosphate group, a sugar {deoxyribose or ribose), and a
nucleobase (adenine, guanine, cytosine, thymine, and uracil).

23
• DNA nucleosides (resulting nucleotide) • DNA nucleotides start with diphosphates
O Adenine + deoxyribose = of RNA nucleotides
deoxyadenosine (monophosphate ----> , Ribonucleotide diphosphate reductase
dAMP) reduces ribose to deoxyribose
O Guanine + deoxyribose = , Molecules then lose phosphate groups
deoxyguanosine (monophosphate----> -->dCM~dUM~dAM~dGMP
dGMP) , Thymidylate synthetase converts dUMP
° Cytosine + deoxyribose = deoxycytidine into dTMP
(monophosphate e- dCMP)
Nucleotide breakdown
O Thymine+ deoxyribose =
deoxythymidine (monophosphate ----> • Pyrimidine rings C,T,U broken down into
dTMP) C02 + NH3, excreted through exhalation/
urine
De novo nucleotide synthesis • Purine rings G,A degraded into uric acid,
• RNA nucleotides start with ribose-5- excreted through urine
phosphate
Salvage pathway
O Then for pyrimidine nucleotides (UMP
and CMP) • Guanine, hypoxanthine from purine
breakdown can be restored into GMP, AMP
O Then for purine nucleotides (AMP and
GMP)

24
 DE NOVO SYNTHESIS of PYRIMIDINES (RNA)
PART 1 ADENOSINE ADENOSINE
TRIPHOSPHATE MONOPHOSPHATE
(ATP) (AMP)

µ·o o o
0 0

·O-

O
I
P-0-C.H
11 µ·o
H
H H
H

OH
~/')
Rl805e: PHOSPHATE
-O-P-0-C.H
I
11
O H H
H

H o-~-o-~-0
I I
OH OH PI/ROPHOSPHOKINASE. OH OH o- o·

RI BOSE-5-PHOSPHATE. PHOSPHORIBOSVL PVROPHOSPHATE

(PENTOSE PHOSPHATEPATHWAY)
( '"'' )

PART~
r- ASPARTATE Ho,11
0

GiLUTAMJNe:+
BIC.ARSONAT£ +
H.,O + ATP
------>--
C..ARBAMOYLPHOSPHATE.
c=o
I
0
----->--
\....
ASPARTATE
H2r
C
c,
yH2
CH
I o? 'w'"'
SYNTHETASE II PO/- TRANSC..ARBAMOVLASE H COOH
( ATGaae)
C.ARBAMOI/L C.ARBAMOI/L
PHOSPHATE:

I
II
,....c.,
HN
0

II
C.H
OIHVOkOOkDTAS< t
ASPARTIC. ACID

0
o
0~c., N
,....c., OROTATE II
I coo .,.....c,
< PHOSPHORIBOSYL-
HN CH
0-~--0-~~ TkANSf~S< I II
c c
4 OH OH
PRPP
o? 'w ... ,
H COO
OROTIDINe: MONOPHOSPHATE.( 01'\P) OROTATE
UMP SYNTHASE.

0 0

HN
...,t,II tH NUC..LEOSIDE HN
...,t,u tH
I n DIPHOSPHATE I II
O At~ tH O O O ?t, tH
KINASE I I I O N .....
o-l-o-Qtor
II ' o
'N...,
) o-ri-o-ri-o-ri-o-Qt,
0
O H H 0 0 0 H H
H H H H
OH OH OH OH
URIDINE. MONOPHOSPHAT£(UMP) URIDINE TRIPHOSPHAT£( UTP )

C..TP SYNTHASE '1,

j·
...,t, i'
...,t,
HN tH HN tH
I U II I
O
o-ri-o-tQ,
O
0 ,.....,
0
H
?t,

H
tH
< O
I
O
I
O
I O
o-ri-o-ri-o-ri-o-Qt,
0
0
0
N .....
tH

0 H
?t,

H
H H H H
OH OH OH OM
C'l'TIDIN£ MONOPHOSPHATe:(CMP) CVTIDINE TP.IPHOSPHATE(GTP)

Figure 3.2 De novo synthesis of RNA pyrimidines. CTP naturally loses phosphate qroups+v CMP. 25
 DE NOVO PURINE SYNTHESIS 0
II
HN""c.,C..,..N'\
C.LUTAMIN£ ASPARTAT£ I II C.H
HC. c I
GLVC.INE
0-1-0-~C.~N/
'N
BIC.AR80NAT£ FORMATE 10-ST£P II • o
PATHWAV O H H
H H
OH OH
IOSINE MONOPHOSPHATE. (IMP)
ASPARTATE

IMP DEMYDROGENASE ADENVLOSUC.C.INATE G,TP

S'lNTHAS€

-ooc.- C.H -C.H- C.OO-

• I
NH
I
Ht,t""C. 'C....- N'\
I II C.H
HC. c I
o-1-0-C.~~N/
'N
II • o
O H H
H H
XANTHOSI NE.
MONOPHOSPHATE OH OH
(XMP) ADE.NVLOSUCC.I NAT£
G,MP
SVNTHAS€ .J.I/ C.LUTAMINE ADENVLOSUC.C.INATEl
L'IAS€

NH1
0
II ! FUMARATE.
Mlf"C.'-C....-N'\ N~ 'c....-N'\ o
I II C.M I II C.H II
o- HC.:::,.. c., I 0'c/c.~c/c.'o
1 M,N,..C,~~~/C....._/
0-ri-O-C.~H~N:
N + ~
0--"-0--C.M, 0
O M M O H H
M M H H
OM OM OH OH

6MP AMP

Figure 3.3 De novo synthesis of RNA purines from precursor iosine monophosphate (IMP).

DNA NUCLEOTIDE SYNTHESIS

o o NUCL£0SASERl80NUCLEOT10E o e NUCL£08AS£
OIPHOSPHATE o-t-o-c.w~NUCL£08ASE
<>-~-o-Lo-<,M,~
II II REOUCTASE>
<>-l-o-i-o-~
II I ' II '
0 0

"
M

OM
M

OM "
0 0
H
M

OM
M

M
H
> O
M
M

ON
M

M
M

U>P/UDP/ ADP/GDP dC 1P/IIUDP/dADP/IIGDP dC P~dAMP/dGMP

THVMIDVLATE
SVNTHE TASE '1j,
I
IITMP

Figure 3.4 DNA nucleotide synthesis from diphosphates of RNA nucleotides.

26
 PURINE BREAICDOWN
0
II
11N"'° c., C.,....N'\
I II C.H r·
N;j<c",c.···'\
i H,N.,C.~~~/C.,/ I/H II
O-P-0-C.H
II ' o o--1-0-~~.., N/C.-
(I ' 0
O H H
O H H
H H H H
OH OH Ol4

&MP AMP

RISO~ ~URINE.NUC.LEOSIDE
PO 2•
•
PHOSPHORVLASE
l
i-NH,
AMP DEAMINASE

GUANINE.

IMP

PURINE. NUC.LEOSIDE ~PO/·

PHOSPHORVLASE ~RISO~
GUANASE

HVPOXANTHINE.
XANTHINE
OXIDASE

X.ANTHINE

'1tI
XANTHINE
OXIDASE

URIC. AC.ID
Figure 3.5 Breakdown of purines into uric acid.

27
 SALVAG.£ PATHWA't'

H VPO)(ANTHI N£ HVPOXANTHIN£ GUANINE

<iaUANIN£
RIBOSE~. PHOSPHORIBOSVL--------:p RIBOSE
TRANSF£RAS£ PO/-
PO/-~
(H6PRT)
0
II
Hr("C.'c...-\,
r-
N~c.,C.,...N'\
0
II
HN"'c.'c...-",
I II C.H I II C.H I II C.H
-<>-1-0-M(.~~N/C...._N/ <>-!-o-:~C.~N/C......./ 1 H,N,,,C.~~f"C...._/
II ' o ',, II ' o <>-ri-0-C.H, 0
O H H ~~~-;;, .... O H H
H H O H H
H H
H H
Oil OH Oil
OH OH

IMP AMP GIMP

Figure 3.6 Salvage pathways that restore AMP and GMP.

28
 NOTES
ama NOTES
PROTEIN METABOLISM

AMINO ACIDS & PROTEIN FOLDING

osms.i"l/ o.mino-o.eids- To-lein-folding

AMINO AGIDS
ALANINE (ALA) (I S = DISPENSABLE
- l"lait. i11 QUANTITV
A"61NINE (ARGi) ~
ASPARAGilNE (ASN) Q METHIONINE (MET) Q , = C,ONDITIONALLV
ASPARTIC, AC,ID (ASP) ~ PHEN't'LALANINE (PHE.) (I E.SS£NTIAL
- "'aclt. MOST of !he.
C.VS E.INE (C,VS) Q PROLINE (PRO) ~ TIME (NOT ALWAYS)
GLUTAMIC AC,ID (&LU)~ SE.RINE. (SER) ~
1 = E.SS£NTIAL
<aLUTAMINE (<aLN) ~ THREONINE (THI') - ,a1111o! Makt.
GL'/C,INE. (&LV) a TR't'PTOPHAN (Ti'P) 4I OURSELVE.S
- OBTAINED fro"'
HISTIDINE (HIS) Q TVROSINE. (TVI') ~ 01.1r DIET

ISOLEUC,INE (ILE) a VALINE (VAL) a

Figure 4.1 The 20 amino acids used by humans.

• Amino acids: organic compounds with

-NH2, -COOH groups [ COOH )-CARBOXVL GROUP
• Side chain gives specific properties SID£CHAIN) I
O Hydrophilic: polar side chains - acidic ®-@)-(ID-HVDROGr£N
(e.g. carboxyl); basic (e.g. amine)
ALPHA CARSON.)~
O Hydrophobic: non-polar side chains -
alkyl, aromatic ~-AMINE. C:.l'OUP
• Molecular charge depends on pH
O Low pH: + amine, 0 carboxyl 0
H H
O High pH: - carboxyl, 0 amine
\/ II
Neutral: + amine, - carboxyl -
O

zwitterion H,s~",e,~"'o-
• Zwitterion: compound with both positive, + I\
negative charges H -N
/\
H
O Occurs in each amino acid at specific pH H H
(AKA pl/isoelectric point)
Figure 4.2 Amino acid structure.
29
• Proteins: amino acid chains connected by
peptide bonds
OPeptide bond: amide bond formed
between amino acids by condensation
of-NH2 with -COOH - releases Hp
O Resonance: electrons shared across
bond - partial double-bond character
- improved strength
• Amino acids: chiral molecules
O Enantiomers/mirror images are distinct
O Proteins only made of L-amino acids
• Protein production occurs in ribosomes
Primary, secondary, tertiary, quaternary
protein structures
• Primary: linear amino acid sequence
connected by peptide bonds
• Secondary: a-helix, [3-pleated sheet
• Tertiary: overall shape, including secondary
structures, with other features (e.g. disulfide
bridge, hydrophobic bonds)
• Quaternary: final level; combination
of multiple amino acid chains (e.g.
hemoglobin)

PRIMAav srauGTUllE.

A~IDE. BOND O llt'\INO AGID5 H )i

~ \ \ ~P~PTll>t BONOS~-}.tr,-/.\
0 \ H, //
<c-, ~ ~ RIM> ,II\ .'£\ o-
H II NAH OH H,"ijf;v-~
I\H
H
'e,...-e,-1 •N
H -, \ SIN<.LE.
H

I\ H H H 80...0S
l( (Jgl(

H-~ H FREEDOl'I ol ROTATION ..)

l H J UGONPARV S TRUGTUll£
GOtlPEtlSATION RE.AcilOtl= OH+ H -+ ~ CX.- HELIX 13- PLEATED SHEETS

Figure 4.3 Amide (peptide) bonds form

H'l'l>ROG,EN
between amino acids through a condensation JOND5
reaction.

CHIMLIT'I'
Lt FT RIGHT
(LE.VO-ORIENTED) (DE.X TRO-ORIENTE.D) T£RTIARY STRUGTUaE
H'/ DROPHOBIC.
AMINO AC.IDS
( COOH] [ COOH]
I I DIS~ O:x~,
~·tt>t
l
f-{-i-r?\
(ID-~-® ®-©-@ 811JDG,t

(NH2)
I
(NH2) H,N
s
0
11!1_1/
- ORIENT TOWARDS tli&
OH INSIDE of th& PROTEIN

t_ ENANTIOMERS .:»

e
r - NOT THE SAME~

e :,i: :~q. QUATERNARYURUGTURt

'I POL'l'PEPTIDE SUBUNITS ----> HEt10GrL081N P"-OTE.IN

Figure 4.4 Enantiomers are two forms
that look like mirror images but are not Figure 4.5 The four levels of structure for
interchangeable, like a left and right shoe. proteins.
Proteins are only made out of levo-oriented
amino acids.
30
 ENZYME FUNCTION
osms.i"l/ en214me-fune-l.ion
• Enzymes: biochemical reaction catalysts MIC.HA£US-M£NTE.N
• Substrates bind to active slte e- enzyme-
substrate complex - t ENZYMES: t vMAX
LL.~ V AAX +--------::=~-----
• Not used up in reactions ~~ +ENZYMES:+ vMAX
• Highly specific (e.g. amylase in saliva ---> !:: t3
large carbohydrate breakdown) 0cx
Ow
~at
>~
t-
TRANSITION
STAT£ CONCENTRATION OF

i
SUBSTRATE [SJ

Figure 4.7 Michaelis-Menten graph: used

to visualize enzyme kinetics. With a fixed
ENZYME. amount of enzyme, the reaction velocity j as
~ substrate is added, until the active sites on
w
z all of the enzymes become saturated. Atthis
w
point, the reaction speed plateaus----> vmax'

REACTION PROGRESS -----+

• K m: substrate concentration when reaction
SUBSTRAT~ PRODUCT velocity is half of maximum

AC.TIVE~
SITE.~ )
® -,
CA) , j enzyme affinity (e.g. activator
molecules) ---> ! Km
, ! enzyme affinity (e.g. competitive
.J SUBSTRATE.- inhibition) ---> j Km
ENZYME. £NZ'IM£ COMPLEX

Figure 4.6 Transition state: intermediate step

in reaction with high energy. Enzymes speed MIC.HA£LIS-M£NTE.N
up reactions by binding substrate (enzyme-
substrate complex). which stabilizes the
transition state and decreases the amount
of extra energy required for the reaction to
proceed. +IC.M: ENZYME 't AFF1N1TY
t IC.M: ENZYME + AFF1N1TY
• Enzyme kinetics: catalysis rate
• Vmax: maximum reaction velocity with fixed
enzyme quantity CONCENTRATION OF
SUBSTRATE [SJ
O j substrate-» j velocity, until all
enzymes bind Figure 4.8 Km is found using a Michaelis-
O j enzymes---> j vmax Menten diagram by identifying~ Vmax on

O ! enzymes---> ! vmax the y-axis, then finding the corresponding

O Non-competitive inhibition (inhibitory substrate concentration value on the x-axis.
molecule binds to active/allosteric site --->
prevents substrate binding)--->! vmax

31
• Lineweaver-Burk plot LINE.WE.AVER-BURK PLOT
O Based on Michaelis-Menten equation
1111181TION
V [S] 1 K +[S]
V. = max - _ = --I!.m'-----'~
o Km+[S] V0 VmaJS]

LINE.WE.AVER-BURK PLOT J_ = I("+ (SJ STIH~ATION

Vo VHAxCSJ

1
I
Vo v,,,,..,. Figure 4.10 Processes that t Vmax ! 1/Vmax

l - the line slopes lower on the graph than

the control. Processes that ! V max i 1/V max -
the line slopes higher on the graph than the
-I 1/CSJ
i; control.

Figure 4.9 The Lineweaver-Burk plot shows

Km and Vmax as functions of the x, y intercepts.

AMINO ACID METABOLISM

osms.i"l/ o.mlno-o.eld-me-1:o.\>ollsm
• Dietary protein broken down into amino Transamination
acids - used to synthesize other proteins • Reversible reaction
O Excess amino acids used for energy/ , Transfers nitrogen-containing amine
stored as fat/glycogen group to another molecule
• Portal vein delivers absorbed amino acids • Amino group transferred (via
(and other nutrients) to liver after uptake by aminotransferase + vitamin B6 cofactor) +:!
small intestine - liver synthesizes needed alpha ketoglutarate (acceptor molecule) -
proteins (e.g. albumin, immunoglobulins), alpha-keto acid + glutamate
non-essential amino acids , Glutamate oxidatively deaminated
• Amino acids delivered to cells throughout in liver mitochondria - ammonia
body via blood - enter cell by facilitated/ byproduct converted to urea (via urea
active transport - used for protein cycle) - eliminated (kidneys)
synthesis (e.g. hormones, enzymes)
• Ammonia (NH/): toxic metabolic by- Deamination
product from amino acid catabolism - • Nitrogen-containing amine group removal
converted to urea (liver) - eliminated (via deaminase) - amino acid utilized for
(kidneys) energy
• Produces ammonia - converted to urea -
renal excretion

LIV£R

Figure 4.11 Ammonia - urea in the liver.

32
 TR"NSAMINATION REACTION
0 0 0

o-~ o- TJl,o-
H3C....,.

o o
" - kE. TOC.LVTI\RAT£ PVRVVAT£
111..ANINE
TI\IINSAMINAS€ (AU")

Figure 4.12 Example of a transamination reaction with amino acid alanine. ALT switches
the amino group on alanine with the oxygen group on a-ketoglutarate, resulting in ketoacid
pyruvate and amino acid glutamate, which has the amino group. Glutamate is the only amino
acid that doesn't have to transfer its amine group to another molecule. It undergoes oxidative
deamination. a process that removes hydrogens and an amino group.

NITROGEN & THE UREA CYCLE

osms.i"l/ntlTogen-o.nd-uTeo.-e14ele
• Ammonia (NHJ: toxic protein catabolism • Glutamine synthetase: NH3 + glutamate -
byproduct; detoxification by liver (forming glutamine
non-toxic urea) • Glutamine transported through blood
• Glutaminase: glutamine - NH3 +
glutamate
AMMONIA • In liver mitochondria

Glucose-alanine cycle
H R • Only from muscle

Hr
\J... I -?o
__, .
·~
G
• Glutamate dehydrogenase:
ketoglutarate - glutamate
NH3 + alpha-

• Alanine transaminase: glutamate+

pyruvate - alpha-ketoglutarate + alanine
H 0- • Alanine transported through blood
• Alanine transaminase: alpha-ketoglutarate
Figure 4.13 Ammonia is composed of a + alanine - glutamate + pyruvate
nitrogen-containing amino group, an acidic
carboxyl group. and a side chain. Glutamate-Nl-l, conversion: two ways
• Glutamate dehydrogenase: glutamate -
NH3 + alpha-ketoglutarate
• NH3 reaches liver in two ways, sometimes ° Free NH3 enters urea cycle
as glutamate • Aspartate transaminase: glutamate
+ oxaloacetate - aspartate + alpha-
Glutamine synthetase system
ketoglutarate
• From all tissues
, Aspartate carries NH3 into urea cycle

33
 H O

@_L_U_1i-AM_A_:r_f)"'~iY'o-
-o~

, ., =-...!•

~=
BLOOP

~LUTAMAT0
@LUTAMINE) H O

H,,r··
'
.. N
o-
H

-o O

A\_.
0-M-MO_N_I~
'·
H-N·•Ulff

LIVER MITOGHONl>RIA
Figure 4.14 The glutamine synthetase system of ammonia reaching the liver.

34
Sk£Lf. TAL MUSGL£ Gf.LL

~:VRUVAT€
0

0 0
-o~o-
oc.-lC.€T06LUTARATE O
/.{Jl
H,,,
T o-ALANINE

(ALANINE) @LUTAMATE)
H,, Y'
'
'·N
I
H O

o- H,,,r
H
'·N ·
O

H
H' o-

-o O

o-
0
G-KETOC:aLUTARATE) ~VRUVAT£)

LIVER GELL

Figure 4.15 The glucose-alanine cycle of ammonia reaching the liver.

35
 GLUTAMATE-NH3 CONVERSION
-- ----------------~~---------
~~ET06LUTARATE.=)
OPTION
#1

OPTION
#2

0 0

-o~o-
o

Figure 4.16 Once glutamate is in a liver cell, there are two possible outcomes for it that depend
on which enzyme it encounters (glutamate dehydrogenase or AST). In Option #1, ammonia
enters the urea cycle; in Option #2, the ammonia group is carried into the urea cycle as part of
the amino acid aspartate.

Urea cycle • Argininosuccinate lyase: argininosuccinate

• Starts in liver cells' mitochondria
• Carbamoyl phosphate synthetase 1 (CPSl)
O NH3 + C02 + 2ATP""""' carbamoyl
phosphate
O N-acetylglutamate""""' rCPSl affinity for
ammonia (by allosteric binding)
• Ornithine transcarbamylase: ornithine
+ carbamoyl phosphate=-. citrulline +
phosphate
• Citrulline moves to cytoplasm
• Argininosuccinate synthetase: citrulline + • Resulting urea then enters blood, excreted
aspartate +ATP""""' argininosuccinate
-vfumarate + arginine
, Fumarate """"' malate; malate
""""'oxaloacetate (by malate
dehydrogenase): oxaloacetate +
glutamate""""' aspartate + alpha-
ketoglutarate (by aspartate
transaminase) """"' aspartate can enter
next cycle
, Arginine""""' urea + ornithine (by
arginase) """"' ornithine can enter next
cycle
by kidneys
36
 ~ACETVL6LUTAMAT~
ADENOSINE C.A"80N
TRI PHOSPHATE DIOXIDE ~~;;;;;;:;:~~
H
H-N'· .. uH
+ j
H

(AMMONIA)

l
MITOCHONDRIA

LIVER CELL
!

{ 0

(ASPARTATE)-):Xo-

(GiLUTAMATE)
(MALATE)

(QXALOAC.ETATE) -11111~:------------~
Figure 4.17 Illustration of the urea cycle, starting with the synthesis of carbamoyl phosphate
from ATP. ammonia, and carbon dioxide, with the help of enzyme CPSl.

37
 PROTEIN STRUCTURE &
SYNTHESIS
osms.i-1:/pTo-l.ein-s-f:.Tue-f:.uTe-C1nd-s14nthesis
• Proteins: functional structures composed of TRANSCR1PT10N
amino acids; synthesized within cells • Messenger RNA (mRNA) transcribes code
• Genes, housed within DNA, provide from DNA
blueprint for protein synthesis • Begins at promoter
• Codon: nucleotide triplet containing , Base sequence establishes transcription
sequence of three nucleotide bases (A. G, starting point
T. C)
° Codes for specific amino acid Initiation
0 64 codons code for 20 amino acids; > • RNA polymerase separates DNA helix at
one codon for most amino acids (UUU, promoter site
UGC code cysteine)
Elongation
O One "start" codon; three "stop" codons
• RNA polymerase unwinds, rewinds DNA -
matches RNA nucleotides with DNA bases
- links them together
NUCLEOBASES
DNA
GUANINE@ ~THYMINE

CYTOSINE gQ ADENINE

"'RNA Figure 4.19 Elongation: RNA polymerase

attaches complementary mRNA nucleotides
to the unzipped DNA template strand to build
GUANINE@ ~ URACIL an mRNA molecule.

CYTOSINE gQ ADENINE Termination

• Ends at termination signal; base sequence
establishes transcription end point
Figure 4.18 The four nucleobases used in
Pre-mRNA formed
DNA are guanine, cytosine, thymine. and
• Contains non-coding areas (introns)
adenine. In mRNA. uracil (U) is used rather
than thymine. , Spliceosomes snip out introns -
functional mRNA
, mRNA complex proteins added - guide
mRNA out of nucleus
38
 TERMINATION of TRANSC,RIPTION
- PIP.NA DE. TACHES
/ RNA POLYMERASE.

TERMINATOP. SE.QUE.NC.€.

>

""t.111s :2 GOMPL£M£NTARY
SEQU£NC.ES 111 a P.OW

TERMINATOP. SE.QUE.NC.€.

..
TRANSCRIBED

Figure 4.20 Termination: when the two complementary sequences in the terminator sequence
get transcribed into mRNA, they bond with each other, creating a hairpin loop that causes the
RNA polymerase to detach from the DNA strand.

TRANSLATION
• Base sequence contained in mRNA
translated into assembled polypeptide

Three RNA types required

• mRNA: carries coded message out of
nucleus to ribosome in cytoplasm
• Ribosomal RNA (rRNA): "workbench" for
protein synthesis
• Transfer RNA (tRNA): brings amino acids
to workbench assembly site at ribosome
° Folded into "cloverleaf" shape
O Acceptor stem: attaches to amino acid
O Anticodon: complementary to mRNA
codon (tRNA binds with mRNA through
complementary base pairing)

39
 afratafreeh.com exclusive

TRANSLATION
rVALINE rGLYCINE
METHIONINE
~~

mRNA
t H Jt J STOP
JCODON
CODONS \
Figure 4.21 Translation: as ribosomes line tRNA molecules up with their complementary codons,
the amino acids held by the tRNA bind with each other to form a protein, which is a chain of
amino acids. The process is terminated at a stop codon.

40