biochem-lipid metabolism 1

8/8/2019 BIOCHEM-Lipid Metabolism 1

1/12

1|P a g e

There is a relationship between intake of carbohydrates

and lipid synthesis. Predominating hormone during

sembreak (eat, sleep, rest) is insulin.

Glucose derived from carbohydrates undergoes glycolysis

and is stimulated in the presence of insulin. There are

enzymes that are induced* with the presence of insulin.

Insulin also stimulates fatty acid synthesis. That is the time

when our cells have the luxury of synthesizing fatty acids

and there by storing them as triacylglycerol. Triacylglycerolis a molecule with glycerol backbones, and in the carbons

of this glycerol are esterified fatty acids.

* Induced/ induction involves 2 processes: transcription and translation.

Wherein in enzymes that are critical for stimulation of glycolysis will be

synthesized in more amounts such as Fructose 1,6-Bisphosphate and

Pyruvate kinase.

** Fatty acid #1 is usually palmitate, Fatty acid #2 is usually oleate, Fatty

acid #3 is oleate or a polyunsaturated fatty acyl group.

I. FATTY ACID SYNTHESIS: Needs activated intermediates that are bound to a

particular molecule, example of the molecule of

which activate intermediates are bound is:

o ACP Acyl Carrier Protein Needs a source of electrons and protons

o NADPH + H coming from hexosemonophosphate (alternative carbohydrate

metabolic pathway) pathway and can also

come from citrate shuttle system (aka

Acetyl-CoA shuttle system)

Found in the cytoplasm, enzymes that will carry thedifferent steps are coming from the cytosol.

To carry on the elongation of carbons to make upthe fatty acid, specifically the palmitic acid, we

need an enzyme complex known as Fatty AcidSynthase Enzyme Complex. After intake a lot of carbohydrates, this will go

through glycolysis producing the pyruvate.

If the cells need energy, pyruvate will be broughtinside the mitochondrial matrix and be oxidatively

decarboxylated to form Acetyl CoA. - oxidation

o Process whereby cells try to degrade fattyacids

o Beta because beta carbon (or carbonnumber 3) is the one involved

Beta carbon is transformed into acarbonyl carbon (carbon attachedto oxygen with a double bond)

First 3 steps utilized bythe cells in order to

liberate 2 carbon

moieties from fatty acids

For cells to degrade fattyacids, 2 carbons should

be removed at a time

General Types of pathways:o Linear pathway

Glycolysis Glucose Pyruvate (or

lactate in a different case)

o Cyclic pathway Krebs cycle

Every turn gives rise toOAA

o Spiral pathway Fatty acid synthesis - oxidation of fatty acid

Every time a cell removes 2 carbon at a time, the cell

utilizes 4 reactions.

Synthesis of fatty acids is the exact opposite ofhow the cells break them down.

Franz Knoop elucidated the different steps initially making

up the - oxidation or the breakdown of fatty acids. Andsince the breakdown of fatty acids is in spiral pathway, he

hypothesized that synthesis of these is exactly in the

opposite way. And later on he was proven right.

Requirements of Fatty Acid Synthesis: Acetyl CoA

o Carbohydrates in the form of glucose afterbeing transformed to pyruvate enters the

mitochondrial matrix to be oxidativelydecarboxylated to form Acetyl CoA

o The one initially utilized to synthesize fattyacids

o Acted upon by an enzyme called AcetylCoA Carboxylase or ACC enzyme Catalyzes the carboxylation

reaction producingMalonyl CoA

SUBJECT: BIOCHEMISTRYTOPIC: LIPID METABOLISM 1 (Chapter 22:Oxidation of Fatty Acids: Ketogenesis & Chapter 23:

Biosynthesis of Fatty acids and Eicosanoids )

LECTURER: Dr. LAYGODATE: 11/23/2010


2/12

2|P a g e

Catalyzes the rate limiting step forsynthesis fatty acids

Single, multifunctional enzyme Requires a biotin group which is

attached to a lysine residue of a

protein molecule

Contains an allosteric regulatorysite

Citrate most importantregulatory factor

Catalyzes the rate-limiting step forfatty acid synthesis which forms

malonyl CoA

Long chain fatty acyl CoAse Inhibits Acetyl CoA

Carboxylase

o Initial building blocko 2-carbon moietyo 16th and 15th carbon of palmitic acid

(most common fatty acid synthesized by

the cell) came from Acetyl CoA and the

rest came from malonyl CoA

CO2in the form ofbicarbonateo Source of carbon

ATPo Source of energy to form a covalent bond

Biotin from biocytino Being a carboxylation reaction wherein the

the source of carbon is CO2, it is the

coenzyme needed by Acetyl CoA

Carboxylase

Malonyl CoAo Utilized by the cell to lengthen the carbons

from Acetyl CoA

o As a result of carboxylation reaction, it is3-carbon moiety

oIt is the source of the 2 carbons used toelongate Acetyl CoA

o In utilizing a 3-carbon moiety, rememberthat the cells only need 2 carbons, so the

other one is liberated as CO2

Question: If the cells will be synthesizing a 16-carbon fattyacid, how many spirals or cycles will the cells need in order

to form palmitic acid (most common fatty acid synthesized

by the cell)?

StructureofPalmiticacid

Remember:o Starting material is a 2-carbon moiety,

Acetyl CoA

16th and 15th carbon of Palmiticacid came from the initial Acetyl

CoA

The rest came from Malonyl CoAo Acetyl CoA Carboxylase (ACC) is only

initially needed to synthesize Malonyl CoA

After the cells have acted uponthe initial Acetyl CoA by means ofAcetyl CoA Carboxylase, forming

Malonyl CoA. Then the fatty acidsynthase enzyme complex willnow take over the process of

elongation.

o Fatty acid synthesis is a spiral pathway.

o We start of Acetyl CoA and we elongatethat by utilizing4 different reactionsutilized by the cell every cycle (every timea cell adds 2 Carbon Moiety to Acetyl CoA):

Condensation 1st Reduction Dehydration 2nd Reduction

Answer:o 7 cycles or spirals needed

We have an original 2 carbonmoiety from Acetyl CoA and cells

try to elongate this by adding 2

carbons at a time (1 spiral/cycle).

So initially 2 carbon moiety plus 2

carbons added per cycle (7 cycles)

is equal to 16 carbons which is

the number of carbon of palmitic

acid. 2 + (2 x 7) = 16

Question: How many NADPH + H will the cells need to beable to synthesize a 16-carbon saturated fatty acid?

Answer: If the cell utilizes 7 cycles, and each of thiscycle involves 2 reduction reactions, it needs 14NADPH + H because each reduction reactionneeds one NADPH + H.

For every cycle, we need 2 NADPH+H because wehave 2 reduction reactions

Malonyl CoA Has 3 carbons Source of 2 carbons used to elongate Acetyl CoA

o We only need 2 carbons, and 1 carbonshould be eliminated in the form ofCarbon Dioxide.

Is taken over by fatty acid synthase enzymecomplex, thereby elongating acetyl CoA to

eventually form palmitic acid.

Signal for the cell to synthesize fatty acidso Its a negative allosteric effector for fatty

acid oxidation

Cells are endowed with a lot ofenergy and therefore can

synthesize a lot of fatty acids

Fatty acid Synthase complex A dimer

o Arranged in a head-to-tail manner


3/12

3|P a g e

A large molecule Multiple domain

It being a dimmer, they are arranged into a head to tailmanner. These subunits carry on the different 4 reactionsthat are utilized by the cell every cycle of the pathway.

Transacylation reaction Initial reaction that attaches and activates

intermediates for fatty acid synthesis to ACP

(Acyl Carrier Protein).

Acetyl transacylaseo Enzyme that catalyzes the binding of

acetyl CoA to the ACP

Malonyl transacylaseo Enzyme that catalyzes the binding of

malonyl CoA to the ACP

Coenzyme Ao Counterpart of Fatty Acid Synthase in

Beta-oxidation

2 reductions and therefore require NADPH+

Needs 7 cycles, 7 malonyl therefore, 14 NADPH+H

Enzymes that catalyzes the 4 different reactions:

Enzyme Product Reactioncatalyzed3-Ketoacyl ACP

synthase

Acetoacetyl ACP Condensation

3-Ketoacyl ACP

reductase

3-OH Butyryl ACP 1st Reduction

3-OHACYL dehydrase Alpha beta trans-

butenoyl ACP

Dehydration

Enoyl Reductase Butyryl ACP 2nd Reduction

We need 8 Acetyl CoA molecules, and then from it, we

synthesize 7 Malonyl CoA), 7 ATP, 14 NADPH+H forming

palmitate, releasing 14 oxidized form of NADP, CoA, water,

and 7 ADP and 7 inogrganic phosphates.

CITRATE During starvation (glucagon and epinephrine are

predominating hormones), if the cells need more

energy, Acetyl CoA will be shuttled to krebs cycle,and will be condensed with OAA, catalyzed bycitrate synthase to form citrate. If the cells are endowed with a lot of energy after a

lot of carbohydrate intake, we will be bombarding

the citric acid cycle with a lot of citrate which

cannot be accommodated by the next step

(aconitase and isocitrate dehydrogenase step), so

excess of citrate will go out into the cytoplasm

(Citrate Shuttle System)

CITRATE SHUTTLE SYSTEM/ACETYL CoA SHUTTLE SYSTEM:

Inner mitochondrial membrane is highly selective. It would

not allow just the entry and exit of molecules. In the

cytoplasm, there will be occurrence ofglycolysis to form alot of pyruvate. Pyruvate goes into the matrix throughpyruvate translocase situated in the inner membrane.Pyruvate in the mitochondrial matrix will then be oxidativelydecarboxylated by pyruvate dehydrogenase (enzymecomplex) to become acetyl CoA. Acetyl CoA will condensewith oxaloacetate to form citrate with the help of citratesynthase. If there is a lot of energy, excess of citrate will goout of the cytoplasm and will be converted back to acetyl-

STOICHIOMETRY OF PALMITATE SYNTHESIS:

8ACETYLCoA +7ATP + 14NADPHPALMITATE + 14NADP++ 8CoASH +6H2O +7ADP + 7Pi


4/12

4|P a g e

coA and oxaloacetate with the help of ATP dependentcitrate lyase enzyme. Acetyl CoA will be acted upon byAcetyl CoA carboxylase to form malonyl-CoA and therebywill be taken over by fatty acid synthase to form fatty acids(such as palmitate). Oxaloacetate will be subsequently

reduced by malate dehydrogenase cytosolic with the helpof NADH to form malate. Malate can either go again insidethe mitochondrial matrix or it can be oxidativelydecarboxylated by malate enzyme (or NADP-dependentmalate dehydrogenase enzyme) with the help of NADP,

which after oxidizing malate back to pyruvate, the cellsgenerate NADPH+H (much needed reducing equivalentneeded for fatty acid synthesis).

Therefore, if we will try to count the number of citrate

molecules that goes out into the cytoplasm, creating acetyl

CoA molecules that the cells utilize for fatty acid synthesis,

How many of this will be generated, that will contribute to

the 14 NADPH+H to complete the synthesis of palmitic

acid ?

NADPH+H = 14 Acetyl CoA needed by the cell to synthesize

palmitic acid = 8

Citrate = 8 (because from 8 citrates, 8 acetyl CoAwill be formed by citrate lyase enzyme)

OAA= 8 converted to pyruvate (8 NADPH+H isgenerated)

***14 NADPH+H 8 NADPH+H = remaining 6 NADPH+H

(which can be provided by HMP or Hexose MonophosphatePathway)

As long as we have citrate in the cytoplasm, Acetyl CoACarboxylase is stimulated.Inactive form Acetyl CoA carboxylase is in the form of

monomers. If there are 40 monomers, they try to aggregate

to form the active form (protein-protein interaction).

There is insulin predominance during FA synthesis. The

confirmation of Acetyl CoA carboxylase is in the

dephosphorylated form (activated form). Insulin and

glucagon are peptide hormones, so they cannot just

traverse the plasma membrane due to the nature of the

structures. For them to be able to transmit their message

inside the cell, they must possess their receptors

expressed on the membrane. Epinephrine (amine hormone)

is derived from tyrosine. The receptor in the plasma

membrane, epinephrine and glucagon have to bind to the

receptor, forming a hormone-receptor complex to activate

the G-protein. Activated G-protein then activates AC

(Adenylyl cyclase), that tries to cyclycize ATP to form the 2nd

messenger, which is cAMP (Cyclic AMP). cAMP activates

the inactive protein kinase A. If there is an activatedprotein kinase A, proteins and enzymes will receivephosphate groups. Therefore, these enzymes and proteinsare inactivated due to their phosphorylation.There is a predominance of epinephrine and glucagon

during starvation. Insulin is exerting the opposite effect of

glucagon. Insulin is also a peptide hormone, which has a

receptor on the membrane. The receptor of insulin is calledreceptor tyrosine kinase. So from this moment, when itbinds, after forming a hormone-receptor complex, one of

the actions is to stimulate an enzyme called

phosphodiestarase (3,5-cyclic AMP phosphodiesterase) to

transform cAMP to 5-AMP. Therefore, protein kinase is notactivated Enzymes will be in the dephosphorylated form.Activated form of Acetyl CoA carboxylase is in

dephosphorylated form, therefore can do its job to

transform Acetyl CoA into Malonyl CoA. But with thepredominance of glucagon and epinephrine, Acetyl CoA isinhibited.Remember: Enzymes catalyze a specific reactions and

therefore specific names:Protein kinase A activation is dependent on cAMP.Protein kinase G activation is dependent cGMP (a second messenger

that activates protein kinase G)

Protein kinase C activation is dependent on calcium ions (C2+)Covalent modification:

Attachment of phosphate group to enzymes andproteins

One way of which the cells try to stimulate/ inhibit2 opposing pathways

o Ex: Glycogenolysis & Glycogenesis(Carbohydrate metabolism)

By attaching a phosphate through glucagon Glucagon and epinephrine 1st messengers (theycan transmit messages inside the cells through

cAMP dependent protein kinase A cascade).

Through covalent modifications whereby activity of

most enzymes are activated, while some are

inhibited.

o So.. Depende sa enzymes.. Merong ibangenzymes na pag naka-tanggap ng

phosphate group, ma-aactivate, meron

naman iba na ma-iinhibit.

Sa ACC, gumagana lang siyakapag dephosphorylated sila. So

dapat walang phosphate group.

o Our cells do not have the luxury tosynthesize molecules when theres a need

for energy. When there is a need for

energy, cells mostly induce catabolism to

release a lot of electrons and protons to

be harnessed in ETC. After being carried

by coenzymes such as FAD and NADH+H.

If we transfer electrons and protons

through NADH+H, it will create a PO ratio


5/12


6/12

6|P a g e

In - oxidation, Malonyl CoA inhibits carnitine acyltransferase 1 (enzyme needed for beta oxidation)

Insulin Induces glycolysis, therefore forms a lot of pyruvate,

a lot of Acetyl CoA, a lot of citrate which cannot be

accommodated by krebs cycle and goes out to the

cytoplasm and is cleaved into acetyl CoA and OAA.

Acetyl CoA will be acted upon by acetyl CoA

carboxylase. More citrate will further stimulate

allosterically your acetyl CoA carboxylase activity,

thereby forming palmitate. When it is activated,

and bound to molecule, forms palmitoyl CoA. From

malonyl to palmitate, we will see the action of fatty

acid synthase complex (FAS).

MOBILIZATION OF STORED TRIAGLYCEROL

Epinephrine, glucagon deactive Protein Kinase A will be

formed and acetyl CoA carboxylase will be phosphorylated

then transforming it into its inactive form. In times of

starvation, we need a lot of energy, and there must be

mobilization of stored triacylglycerol. In the presence ofglucagon and epinephrine, through cAMP dependentprotein kinase cascade, there will be phosphorylation ofhormone-sensitive lipase (sensitive to glucagon andepinephrine). So now, these hormone sensitive lipase being

phosphorylated, thereby activated, will now try to hydrolyzetriacylglycerol into fatty acids and eventually into glycerolbackbone. Fatty acids will be carried into circulation. And in

the circulation, will be carried by albumin protein. 6

molecules of fatty acids in 1 albumin, going back to the

liver and is subjected to Beta-oxidation.

TRANSPORT OF FATTY ACIDS IN THE BLOODSTREAM:1. PLASMA ALBUMIN

a. Major carrier of free fatty acids in bloodb. Binds ~6 molecules of fatty acids per 1

molecule of albumin

c. Also binds and transports bilirubin, otherorganic anions, and a variety of xenobiotic

compounds (aspirin, barbiturates,

Coumadin, oral hypoglycaemic agents)

2. LIPOPROTEINSa. Carriers of esterified fatty acids, primarily

as triaglycerols

Lipoproteins, specifically chylomicrons which carry dietarytriacylglycerol, while VLDL carries the endogenously

synthesized triacylglycerol into the circulation.

TRANSLOCATION OF FATTY ACIDS INTO MITOCHONDRION

Lingual lipaseinitial digestion of lipids in the mouthChyme goes down into duodenum and stimulates the

secretion of pancreatic juice. Chyme contains

lipids/triacyglycerol, proteins, carbohydrates so there is a

variety of enzymes that permits digestion. In this lecture,


7/12

7|P a g e

we will focus on the enzyme, PANCREATIC LIPASE since it isthe one responsible for lipid digestion.

Pancreatic lipase acts on dietary triacylglycerols whichpermits the release 2 free fatty acids and a 2-

monoacylglycerol (there is still a fatty acid esterified at 2nd

carbon of glycerol backbone). Pancreatic lipase is stabilizedby colipase. Before the action of pancreatic lipase, there isan initial step in which the cells have a way to decerase the

lipid-water interphase so that the hydrophilic enzymes can

interact with hydrophobic triacyglycerols (lipid droplets),

which we call emulsification. After that, pancreatic lipasetakes effect.

Upon the breakdown, the fates ofshort and medium chainfatty acids will be immediately transported into thecirculation, and will undergo oxidation in the mitochondrionof the liver cells. While long chain fatty acids together with2-monoacylglycerols (after absorption by intestinal cells),

they will resynthesize triacylglycerol inside intestinal cell

and will be given a coat of apoliprotein B48 to formchylomicrons and to which the chylomicrons transport them

to the lymphatic system and will eventually be emptied into

the thoracic duct and then to subclavian vein.

Fransup said that FA must be degraded by removal of 2

carbons at a time, which occurs in mitochondrion (by

Leninger). And 2 carbons released is not acetate, but

acetyl-CoA (FA synthesis is also called as Linen Cycle)

BETA-OXIDATION OF FATTY ACIDS Beta carbon is the one involved in the process of

cleavagei. By transforming this 3rd carbon into

carbonyl/carboxyl carbon

ii. Done by the 1st 3 steps exactly opposite ofthe Fatty Acid synthesis (Condensation,

Reduction, Dehydration)

1. Oxidation2. Hydration3. 2nd Oxidation4. Cleavage

Cells liberate phenylacetate true for even chainfatty acids

Cells liberate benzoic acid true for odd chainfatty acids

Cell degrade fatty acids by removal of 2 carbons ata time

For fatty acid oxidation:i. Molecule attached to intermediate is attached

by Coenzyme A (counterpart of transacylase infatty acid synthesis) which is carried out byAcetyl CoA Synthetase

ii. 2-step reaction1. ATP is hydrolyzed to AMP +

Pyrophosphate

2. Pi is hydrolyzed by pyrophosphataseto liberate 2 Pi

a. Energy liberated by 1 mole ofPyrophosphate being

hydrolyzed to Pi = -6.6 kCal

i. If this is the kind ofhydrolysis carried out,

it amounts to 2 moles

of ATP

ii. Hydrolysis ofpyrophosphate to 2

inorganic phosphates

ensures the

completion of the

reaction.Acyl CoA Synthetase Also known as thiokinase Catalyzes the activation of acyl groups, forming

acyl CoA

Ex: Palmitic acid + Coenzyme A Palmitoyl CoAo Can now be allowed to enter the matrix.o Acted upon by Carnitine-Palmitoyl

transferase 1

CARNITINE PALMITOYL TRANSFERASE 1Allows the transfer of acyl group to carnitine to form acyl

carnitine, subsequently releasing coenzyme A. As acylcarnitine, it can now be translocated inside the matrixthrough the help of a protein embedded in the inner

mitochondrial membrane, which is named as carnitine-acylcarnitine translocase. Inside the matrix, this acyl carnitinewill be subsequently acted upon by carnitine-palmitoyltransferase 2, transferring acyl group back to Coenzyme A,releasing carnitine. Carnitine will be translocated outsideinto the intermembranous space, by means of the

translocase, in time for the second load of palmitoyl-Coa

**Carnitine-Acyl Transferase 1 is just a general name, while Carnitine-

Palmitoyl Transferase 1 is a more specific one.

PROTEINS FOR FATTY ACID TRANSPORT

Site of action of malonyl CoA inhibits carnitine-palmitoyltransferase 1. Carnitine-palmitoyl transferase 1. MalonylCoA is the rate limiting for beta-oxidation.

Carnitine is a molecule is synthesized by liver and kidney

cells from Lysine and Methionine. In the biostatic pathway,there are 2 enzymes that need the coenzyme vitamin,

ascorbic acid.Different steps repeated every cycle in the pathway of B-oxidation:


8/12


9/12

9|P a g e

2 kinds of unsaturated fatty acids:1. Monounsaturated Fatty Acids

Initially,thereisadoublebondsituatedincarbon9and

10.Initially,

oleoyl

CoA

is

subjected

to

3cycles

of

normal

Boxidation.Afterremoving6carbons,theinitialcarbon

7becomescarbon1,carbon8nowbecomesouralpha

carbon,andcarbon9becomesthebetacarbon.Thebeta

carbonaswecanseeisnowinvolvedinadoublebond,

whichourcellswillnotbeabletoutilizethecarbonwith

doublebond.Sothecellsisomerizes cisdelta3

DodecenoylCoAformingtransdelta2DodecenoylCoA,

whichcanbesubsequentlyhydratedwithamoleof

watertoformLbetaHydroxyDecanoyl.Afterthiswe

cannowutilizethenormalBoxidationcycletodegrade

thiskindoffattyacid.

2. Polyunsaturated Fatty Acids2 double bonds are seen between carbons9 and 10, 12 and 13 and they undergo 3

cycles of beta-oxidation. Afterwhich, the

beta carbon is again involved in a cis

confirmation of double bond. By means of

an isomerase, it can be transformed into a

trans-delta-2-enoyl CoA.

Cells use isomerase initially, then

dehydrogenase, and lastly reductase so

that normal B-oxidation of polyunsaturated

fatty acids may be take place.

PEROXISOMAL OXIDATION Flavin-dependent reaction Amount of energy in the form of ATP is less

because electrons are not transformed to ETC, but

instead transferred to a molecular oxygen, forminghydrogen peroxide Hydrogen peroxide is a harmful compound that is

degraded to oxygen and water by the catalaseenzyme.

ALPHA OXIDATION Oxidizes branched chain fatty acids We derive metabolite intermediate coming from

chlorophyll (phytanic acid), a branched chain of

fatty acid.

May also be a source of energy.

Carbon number 1, Carbon number 2 (alpha carbon), Carbon number 3

(beta carbon) has a methyl substituent; ourcells do not have an enzymeto act upon the beta carbon with a methyl substituent. The cells thenutilize alpha oxidation, wherein the alpha carbon will be the carbonyl

carbon, and the carbon number 1 is liberated as CO2. When carbon 1 isremoved, the former alpha carbon becomes the carbon number 1, and

the former beta carbon will not have branch. So therefore, this can be

subjected to the 4 steps that are repeated every cycle of the pathway.

If that is the case, the cleavage will be at the site wherein it releases

propionyl CoA (a 3-carbon moiety). Propionyl CoA is transformed to

Succinyl CoA and eventually enters Krebs cycle. Beta carbon can be

subjected to a normal beta oxidation, releasing Acetyl CoA (2-carbon

moiety). After that, it releases propionyl CoA again.

Refsuns Disease refers to the accumulation of phytanicacid especially in the brain, secondary to enzyme

deficiencies.

OMEGA OXIDATION Last carbon or the omega carbon is transformed

into a carboxylic carbon.

o If this happens, both sides can besubjected to normal B-oxidation

SHORT TERM REGULATION FOR FA METABOLISM:

Glucagon and Epinephrine phosphorylate theacetyl CoA carboxylase, which forms cAMP which

then activates protein kinase A and therefore

phosphorylates, ACC, inhibiting its activity.


10/12

10|P a g e

o So instead of FA synthesis, thepredominant pathway is beta-oxidation,

forming a lot of acetyl Coa. Acetyl CoA

goes to krebs cycle.

After oxidation, cells form a lot of ketone bodies. And if cellis in starvation, the source of energy is from Acetyl CoAthen the cell forms a lot of ketone bodies. Condensation of2 moles of Acetyl CoA catalyzed by thiolase, with therelease of coenzyme A forming acetoacetyl CoA. By means

by synthetase and with another mole ofAcetyl CoA, we willform 3-hydroxy-3-methylbutaryl CoA, with the release ofacetyl CoA, we form the 1st ketone bodyacetoacetate.Acetoacetate forms acetone.

Acetone A volatile ketone body which is released through

respiration.

Its accumulation may also result to type 1 diabetesmellitus which has the propensity to develop

ketoacidosis due to the absence of insulin

synthesis.

3-hydroxy Butarate Another ketone body

Acetone + dehydrogenaseLiver is the site of ketogenesis. But with respect to energy

utilization, the liver cannot utlize them as source of energydue to the absence of succinyl CoA -aceto-acetate CoAtransferase (thiophorase). Ako ang nag saing, iba ang kumain.

Awww Emo much:(

EICOSANOIDS Autocrine (the same cell that secretes the

hormone will be the one affected) and paracrinehormones (adjacent cells will be the ones that willbe affected).

Example: Prostaglandins, leukotrienes, thromboxanes, lipoxins

Synthesized fromo 20-carbon FA (AKA eicosanoic acids)

Arachindonic (4 double bonds)series 2 prostaglandins (through

cycleoxygenase pathway)

Timnodonate (5 double bonds) Eicosapentaenoic acids series

3 prostaglandins

Eicosatrienoate

Exert their effects through formation of cAMP.

They have to bind to the receptor in the plasmamembrane which stimulates the G-protein which

activates Adenylyl Cyclase, which forms cAMP out

of ATP (cAMP protein dependent kinase cascade).

Physiological responses:

Negates inflammatory responses Produce pain and fever Regulate blood clotting Induce labor (for specific kinds) Have an effect on regulation of split weight cycle Inhibits gastric secretions Stimulate contraction of intestinal smooth muscles

PROSTAGLANDIN Identified in human semen and other cells Prostaglandin E and Prostaglandin F are initially

discovered

Derived from hypothetical prostanoic acid There are 3 major classes (depending on the

structure):

o Prostaglandin A ,- unsaturatedketones

o Prostaglandin E-- hydroxy ketoneso Prostaglandin F- 1,3 dioles (2 hydroxy

groups)Series 1 prostagalinds there is 1 double bond outside thecyclicized region from eicosatrienoic acid or dihomo-gamma-linolenic acidSeries 2 prostaglandins there are 2 double bonds outside

the cyclicized region from eicosatetraenoic acid orarachidonic acid


11/12

11|P a g e

Series 3 prostaglandins there are 3 double bonds outsidethe cyclicized region from eicosapentaenoic acid ortimnodonic acidAmong the unsaturated fatty acids, there are 2 essential

polyunsaturated acids:

1. linoleic acid (true essential)a. From this, we can synthesize dihomo-

gamm-linolenic through adehydrogenation reaction2. linolenic acid

LEUKOTRIENESo Catalysis through lipooxygenase

o Series 3 from eicosatrienoateo Series 4 from arachidonic acido Series 5 from eicosapentaenoate

Arachidonic acid is the most important precursor.

o Generation of Arachidonic acid through:o Reaction ofphospholipase A2 which acts

on carbon 2 of glycerol backbone.

o Phospholipase A1 acts on carbon 1 ofglycerol backbone

o Phospholipase C acts on carbon 3o Phospholipase D removes the base.

Ex: Enositol portion ofphosphatidyl enositol is removed

through this phospholipase D.

o Diacylglycerol lipaseo Diacylglycerol kinase

Phosphatidyl enositol through phospholipase A2

arachidonic acid + lysophospholipid

Diacylglycerol kinase + phospholipase C phosphatidic

acid (+ phospholipase A2 arachidonic acid)

Diacylglycerol lipase from 1,2 diacyl glycerol arachidonic

acid

2 major pathways of arachidonic acid metabolism:1. Cyclooxygenase (Cyclic pathway)2. Lipooxygenase (Linear pathway)

Shows us how Arachidonic Acid Prostaglandin

o 2 activities:

o Cyclooxygenase activity is inhibited byaspirin (acetylsalicylic acid) and ibuprofen

(Non-steroidal anti-inflammatory drugs)

2 isoforms of cyclooxygenase COX1 a constitutive

enzyme (its always

present whether or not

there are substrates)

o When blocked,GI bleeding and

gastritiso Needed for the

maintenance of

integrity of the

membranes of

intestinal cells

COX2 an inducibleenzyme

o Made only inresponse

through

inflammatory

initiators such ascytokines

o The one that isblocked

o Celecoxib arespecific

inhibitors

o Cyclooxygenase activity is inhibited byaspirin and ibuprofen (Nonsteroidal anti-

inflammatory drugs)

Pathway for Cyclooxygenase:o Prostaglandin H2 synthase enzyme complex:

o Possesses: Cyclooxygenase activity

Aspirin inhibits thisactivity

Peroxidase activity

Structure of cyclooxygenase domain has 3 important amino

acid residues

1. Tyrosine 3,8,5a. Forms a radical in the process of forming

prostaglandinsb. If we give NSH, it will affect the tyrosine

residue that prevents the formation of

radical

2. Serine 5,30a. Aspirin acetylates this, producing acetyl

moiety which blocks the whole entry of

arachidonic acid

3. Arginine 1,20a. Forms an ion pair with substrateb. If arachidonic acid cannot enter, arginine

cannot forms an ion pair with substrate

Phospholipase A2 generates arachidonic acid

o Hormones that stimulate angiotensin 2:o Bradykinino Epinephrineo Thrombin

o Cortisol (principle corticosteroid) inhibits theactivity of phospholipase A2


12/12

12|P a g e

Prostaglandin dehydrogenase

o Carbon attached to hydroxyl group is subsequentlyoxidized, and therefore inhibits prostaglandin

LIPOOXYGENASE PATHWAY

o Peptidoleukotriene mediates anaphylaxiso Leukotriene C4o Leukotriene D4o Leukotriene E4

o WBC, Muscles, Lungs, Braino Actions:

Induces release of lysosomal enzymes Promotes adhesion of WBC

o Message is transmited by the formation of 2ndmessenger of cAMP

LIPOXINS

Family of congregated tetraenes Vasoactive and immunoregulatory effects

-----------------------END OF TRANSCRIPTION-------------------------------

Kung hindi clear yung image, please refer to the uploaded

pdf file if it is available

biochem-lipid metabolism 1

Documents