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Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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Page 1: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط
Page 2: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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( nabeel doctor speech( اما ) nabeel slide) لتميز كالم الدكتور عن الساليدات

بالشيت للي بطبعوا طباعة و الكالم الي ملون باالحمر بالساليدات رح يكون تحته خطين

From the last lecture

• Acetyl CoA can give pyruvate in plants not in mammal, why ?

[[Remember -- the Source of Acetyl coA is carbohydrate, lipid & protein]]

Because Mammal can't change/turns lipid to glucose

glucose ليعطي ال pyruvateو بعدين بحوله ل acetyl coAبعطي lipid))يعني لو كان ال

this is wrong case النهMammal can't change lipid to glucose ))

& The reaction ( pyruvate to acetyl coA ) IS IRREVERSIBLE

• Fat degradation lead to give fatty acid & glycerol not glucose

• Mammal can convert pyruvate to oxaloacetate by pyruvate carboxylase (an enzyme

activated by acetyl-CoA)

• When pyruvate give oxaloacetate not acetyl coA??

When gluconeogenesis take place it will consume oxaloacetate ( oxaloacetate convert

to PEP & so on …) So there will be no enough oxaloacetate to enter CAC cycle , so

pyruvate convert to oxaloacetate in reaction called

Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction pyruvateال عبر ايجاده من oxaloacetate التعويض ل استهالك ال

Page 3: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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• Oxaloacetate come from pyruvate & malate SO CAC cycle take place at the same time that

gluconeogenesis take place (( energy production take place at the same time

gluconeogenesis take place ))

• Loss weight can be easily if the fat convert to glucose but its unfortunately impossible ,so to

lose your weight ( 0.5 kg ) you have to walk 30 km (☺ فوتوا " لو نفسك تخس" اسرع (

• This citric acid cycle give intermediate in other metabolite

Biosynthetic Roles of the Citric Acid Cycle. Intermediates drawn off for

biosyntheses (shown by red arrows) are replenished by the formation of

oxaloacetate from pyruvate.

Page 4: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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New chapter: ~

❖ The Role of Electron Transport in Metabolism

Electron transport is carried out by four closely related multisubunit membrane-bound

complexes and two electron carriers, coenzyme Q and cytochrome c

o In a series of oxidation-reduction reactions, electrons from FADH2 and NADH are

transferred from one complex to the next until they reach O2 (final e acceptor)

o O2 is reduced to H2O

o As a result of electron transport, protons are pumped across the inner membrane to

the intermembrane space, creating a pH gradient

• The ultimate aim for electron transport metabolism is

1. Production of energy

2. Production of water

• The production of ATP in mitochondria is the result of oxidative phosphorylation this mean that ATP

which produce by electron transport chain is more than ATP that produce from glycolysis or CAC cycle

ETC وال اشي مقارنة بالطاقة من ال glycolysis الطاقة من ال

• NADH & FADH2 ( للغشاء الداخلي للميتوكندرياتوصل االلكترون is electron carrier ( للمرة المليون

• The most membrane in mitochondria have proteins is inner membrane of mitochondria و يشبة بالمسبحة

Because it the power house to the cell , it energy producing site to the cell

• We have two electrons carrier is coenzyme Q & cytochrome C

❖ ATP Production in the Mitochondrion

The production of ATP in the mitochondria is the result of oxidative phosphorylation

The proton gradient establishes a voltage gradient the process of transporting the electrons gives

energy for pumping the protons from the mitochondrial space to intermembrane space and this make VOLTAGE

GRADIENT

The proton and voltage gradients together provide the mechanism to couple electron transport with

phosphorylation of ADP because that we said :- production of ATP depend on ADP concentration, in

exercise state ADP in high level so you need ATP. But if ATP in high level, the energy will storage in your body

• The ETC take place in inner membrane mitochondria

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• The CAC cycle in matrix of mitochondria

• The gluconeogenesis & urea cycle between the cytosol & mitochondria

❖ Establishment of the Proton Gradient

• the process of transporting the electrons gives energy for pumping the protons from the mitochondrial

matrix to intermembrane space and this make PROTON GRADIENT & high concentration of H+ in the

intermembrane space low pH

• the process of transporting protons from the innermembrane to matrix make phosphorylation to ( ADP to

ATP)

❖ Electron transport from one carrier to another

creates a proton gradient across the inner

mitochondrial membrane

❖ The proton gradient is coupled to the production of

ATP in aerobic metabolism

• ETC how oxidative phosphorylation ?

By 4 protein complexes & 2 electron carrier ( Co Q & Cyt

C )

• Why NADH produce 3 ATP but FADH2 produce 2 ATP??

because NADH start the cycle from the beginning it start

from complex one , & it pass through complex 1&2&3 ,

FADH2 inter the cycle in complex 2 to complex 3

Page 6: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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The 4 respiratory complexes

• Each complex is composed from several proteins and enzymes

• Complex one Consists of Flavin mononucleotide , iron-sulfur cluster electron come from NADH to

complex 1 & go to CoQ ( carrier ) CoQ carry electron to complex 3 then go the Cyt C ( carrier) Cyt C

carry electron to complex 4

بين مين ومين carrier الي بالمربعات و انتبهوا لمواقع ال complexتبعوا الرسمة و احفظوا اسماء ال

• Fe-S cluster reduced & oxidized

• FADH2 come from succinate fumarate

• Succinate dehydrogenase is the only CAC cycle enzyme attach to inner membrane to metochandria & it

contain heme group

طبعا هون الموضوع اكبر من هيك بس هاد الي حكاه الدكتور •

Page 7: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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❖ Compositions and Locations of Respiratory Complexes in Inner Mitochondrial

Membrane

• NADH in matrix come from CAC cycle ( which produce 3 NADH & 1 FADH2 & 1GTP )

• Electron of NADH inter to complex one and react with FMN then FeS reduced & give the 2 electrons from

complex one to CoQ one of these electron go to complex 3 and another electron inter Q cycling ( Cyt b1

to Cyt bH ) then back to CoQ

( ( CoQ carrier that recycle Cyt b1 to Cyt bH to take another electrons and deliver them again) )

• Then the electron ( which stay in the complex one ) react with Cyt C1 then go to Cyt c

[[Note Cyt C is carrier outside the membrane, carry electrons from complex 3 to complex 4

BUT Cyt C1 found inside complex 3 ]]

[[Note CoQ embedded in membrane BUT Cyt C outside the membrane ]]

• Cyt C carry electrons to complex 4 which have Cyt a & Cyt a3 , electrons leave complex 4 & react with H+ to

form H20

Page 8: Pyruvate Oxaloacetate Fell Up reaction or Anaplerotic reaction · Page 1)nabeel doctor speech ( اما ) nabeel slide ( تادϴϽسلا نع روتكدلا مϽك زϵمتل ةعابط

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The Heme Group of Cytochromes

Oxidative Phosphorylation

• the energy-releasing oxidations give rise to proton pumping and a pH gradient across the inner

mitochondrial membrane

• in addition, differences in the concentration of ions across the membrane generates a voltage

gradient

• a coupling process converts the electrochemical potential to the chemical energy of ATP

(phosphorylation)

All cytochrome proteins contain a heme group (red

colour )

There are differences in the side chain depending

on the heme

What is the different between heme group to cytochrome

& hemoglobin & myoglobin??

In hemoglobin & myoglobin bind to O2

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• the coupling factor is ATP synthase, a complex transmembrane protein oligomer, separated

from the electron transport complexes

• P/O ratio: the number of moles of Pi( inorganic phosphate) consumed in phosphorylation to the

number of moles of oxygen atoms consumed in oxidation

⁕ P/O = 3 when NADH is oxidized

⁕ P/O = 2 when FADH2 is oxidized

Summary

The coupling of electron transport to oxidative phosphorylation requires a multisubunit membrane-

bound enzyme, ATP synthase. This enzyme has a channel for protons to flow from the

intermembrane space into the mitochondrial matrix.

The proton flow is coupled to ATP production in a process that appears to involve a conformational

change of the enzyme

Peter Dennis Mitchell, (1920-1992)

was a British biochemist who was awarded the 1978 Nobel Prize for Chemistry for his

discovery of the chemiosmotic mechanism of ATP synthesis

ATP-Production كان كل اإلعتقاد في الستينات إن ال Mitchell قبل

substrate levelاللي هو succinyle coA succinateتبع reactionزي substrate level phosphorylationبصير على

phosphorylation.

Protonاكتشف انو في اشي اسمه Mitchellمش بحاجة إلى مكان آخر، بعدين بعد بحوثات ATP-Productionكان اإلعتقاد انو

gradient وفي اشي بحصل بmitochondrial itself وبحصل فيinner membrane of mitochondria نتيجة الproton

gradient نتيجة فرق فيconcentration of protons في الmitochondria matrix and intermembrane space ومن هون

بصير التفاعل.

ADP + Pi ATP + H2 O

1 / 2 O2 + 2 H++ 2 e - H2 O

Phosphorylation (P)

Oxidation (O)

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Chemiosmotic coupling

Chemiosmotic coupling: Coupling Ox to Ph (oxidative to phosphorylate )يعني عمليتين مع بعض

It is based on a proton concentration gradient between the intermembrane space and the matrix.

.concentration between intermembrane space and matrixمهم, الفرق في gradientهذا ال

In addition to electron transport, these proteins of ETC (ETC→ Electron Transport Chain) take up protons

from the matrix when they are reduced and release them to the intermembrane space when they are

reoxidized.

-_-كيف بصير هذا الحكي، طبعا النوا حنا بنقتنعش بالكالم والزم نشوف صور...

Creation of a proton gradient

proton في نفس اللحظة بدو يصير electron transport between membrane protein(complex I,III,IV) اول اشي بدو يصير

pump from mitochondrial matrix to intermembrane space يعني انتقال االلكترونات مصحوب ب ,proton pump .

.intermembrane spaceبدها تطلع في ال matrix هاي البروتونات اللي جوا ال

Complex I 4 بدو يطلع protons

Complex III → 2 proton

Complex IV → 2 proton

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Electron transport يصحبها proton pump رح يطلع من mitochondrial matrix للintermembran space رح يؤدي إلى

high gradient in intermembrane space وال ,high gradient رح تؤدي إلىproton flow back into the matrix through

ATP-synthase و رح يؤدي إلىphosphorylation فيADP to form ATP

Mechanism of Ox/Phos

Synthase

ATP-synthase عبارة عن oligomer 8يحتوي على-subunit (α,β,ε,σ,γ)

main: F1-subunitل وفيه ا

F0-subunit

عشان يعملو protonsألنه من خالله رح يمروا ال inner membrane of mitochondria موجود في الهذا أكثر بروتين

phosphorylation ولذلك هو يعتبر من اإلنزيمات المهمة ألنو بدونه ما رح يصير ،ATP-Production

• The mechanism by which the proton gradient leads to the production of ATP depends on ion channels through the inner mitochondrial membrane

• protons flow back into the matrix through channels in the F0 unit of ATP

synthase

• the flow of protons is accompanied by formation of ATP in the F1 unit of

ATP synthase

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.ATP-synthaseاللي بتكون هون بترجع عن طريق proton gradientليش؟ ألنه ال

F0 موجود في ال membrane والF1 موجود جوا الmitochondrial matrix إلى سيؤدي , هجوم البروتونات

phosphorylation of ADP.

Mechanism of Ox/Phos

. increase proton(high gradient)بالتالي هون في

Chemo of model theory بقلك انو فيdifference in concentration of proton between

intermembrane space and matrix إلى سيؤدينتيجة هذا اإلختالفpumping of protons to mitochondrial

matrix to phosphorylate ADP to form ATP to process electron transport لحالها وبعدين

phosphorylation ADP to form ATP

Mechanism of Mitochondrial ATP-ADP Translocase

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ATP بتكون في mitochondrial matrix بس احنا ما بدنا إياها في ال matrix بدنا إياها فيcytosol بالتالي في عملية اسمها

Translocation انو الATP اللي بتكون في الmitochondrial matrix بدو يطلع برا إلىcytosol واللي هناك رح يصير

matrix ويدخله لل cytosolاللي في ADP هذا اإلنزايم رح يجيب ال ATP-ADP translocaseالتفاعل، فبالتالي هناك انزايم اسمه

. cytosol لل هويطلع matrix اللي بتكون في ال ATPوياخذ محله

OX-PHاللي بتكون في matrix، رح يجيهم من ال ATPهذول من وين رح يجيهم ال Hexokinase and PFKaseالخطوتين تبع

. phosphorylation رح يطلع لبرا عشان يعمل

Respiratory Inhibitors

Rotenone

is an odorless, colorless, crystalline isoflavone used as a broad-spectrum insecticide, piscicide( fish

poison), and pesticide.

. poisoning in humanهذول بستخدموهم كمبيد حشري وكمان لألسماك ، إذا لم يحسن استخدامهم يؤدي إلى

Amytal,

also known as amobarbital or blue heavens, is a barbiturate, and is occasionally used to treat

insomnia االرق , tension, and anxiety disorders. Doctors also sometimes prescribe barbiturates for the

nerve disorder known as epilepsy الصرع

. electron pulsesنخفف energy عشان يخفف ال

Rotenone and amytal inhibit complex 1 يعني بمنعواNADH انو يعطي االلكترونات تبعتو بس ما منعوا االلكترونات انها

.reduced production of energyفهون رح يصير FADH2تيجي من

FMN

CoQ

Fe-S

Cyt c 1

Cyt aa3

O2

Cyt b

rotenone and amytal

myxothiazol

CN- , N3-, CO

Cyt c

antimycin A

NADH

UHDBT

ل inhibition ايش اللي بدو يعمل

respiratory ؟

electron transport system، انك تّموت

رح inhibitors كل واحد من هاي ال

تنشرح تحت لحالها

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Potenone & amytal make inhibit in complex 1 so prevent NADH to give his electron but don’t prevent electron

from FADH2 so this make reduce production to energy

Antimycin A:

It was first discovered in 1945 and registered for use as a fish toxicant in 1960.

Myxothiazol → another drug

UHDBT: HYDROXYDIOXOBENZOTHIAZOL; 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole

.iron-sulfer cluster and cytochrome c1 in complex 3للخطوة بين inhibitهذا بيعمل

Cytochrome oxidase (cytochrome a3) his subunit contain : cyanide(CN-) , Azide(N3-), carbon

monoxide(CO)

Cyanide : highly toxic , lethal dose (50 mg) ( one drop)

طبعا هو كويس ألنه إذا استخدم في جريمة )قتل مثاًل( ال يكتشف ، يعني الواحد بموت مرتاح بسرعة وال يكتشف في الدم وتأثيره

هاي لما ال.. زي الدراق مث (هذا موجود في بذور بعض الفواكه، البذور الصلبة )مش اللوز cyanideممتاز وبعدين وجدوا انو

^-تنطحن بتعملوه على شكل باودر يعني زي السكر المطحون وبترشه ع الكيك وصحتين وعافية ^

. ☺ احسن طريقة لإلنتقام cyanideوبالتالي بنستنتج انو

اغالق المنافذ جميعها مع عن طريق اشعال الصوبة COبال م حالك وا" = اخنقمع راحة تامة بدون الـم " واذا بتحبوا الموت

☺و موتا هنيئـــــاً اعزائي

Azide بكون موجود في المعلبات كمواد حافظة اللي بتحافظ على االكل يظل زي ما هو وتعتبر من المواد المسرطنة

السامة.

Regulated Uncoupling Leads to the Generation of Heat

The uncoupling of oxidative phosphorylation is a means of generating heat to maintain body

temperature in hibernating animals, in some newborn animals (including human beings), and in

mammals adapted to cold. Brown adipose tissue.

تمشي بس ما في إنتاج ل electronإلى انو ال سيؤدي ATP productionوما وصلتش ل electron transportهسا لو ما مشت ATP وهذا يحصل فيadipose tissue إلى سيؤدي ألنه, generation of heat إلى يؤدي انتقال االلكترون لحالهاproduction of

heat. Brown adipose tissue موجود فيhibernating animals + babies موجود في المحالت المعرضة إنها تتكشف بالنسبة لل

baby.

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It is specialized for this process of nonshivering thermogenesis. The inner mitochondrial membrane

of these mitochondria contains a large amount of uncoupling protein (UCP), here UCP-1, or

thermogenin.

ATP فبالتالي ما في ATP-synthase برجعهم مرة ثانية ما بوصلهم لل intermembrane spaceكل ما يتكون بروتون في ال

production بس فيه انتقال لإللكترون والبروتون بيأدي إلىproduction of heat استخدموا العملية هاي وحكوا طالما انو الجسم,

انو يرجع لل proton تساعد ال chemical uncouplers إذًا دوروا على مركبات بسموها ATPبيستطيع ينتج حرارة بدون

mitochondria وما يتكون ATP ,and this will produce loss of weight.

To Fast loss of weight use 2,4- Dinitrophenol

استخدموه عشان البرد وعشان الجنود يتدفوا والممثالت والناس اللي بدها الروس)استخدموه بكثافة في الحرب العالمية الثانية ,

وزنها ما يزيد، طبعا إذا استخدم لفترة طويلة ممكن يأدي إلى الموت.(

UCP-1 forms a pathway for the flow of protons from the cytosol to the matrix. In essence, UCP-1

generates heat by short-circuiting the mitochondrial proton battery

Action of an Uncoupling Protein. Uncoupling protein-1 (UCP-1) generates heat by permitting the

influx of protons into the mitochondria without the synthesis of ATP

THE END

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