pyruvate oxaloacetate fell up reaction or anaplerotic reaction · page 1)nabeel doctor speech (...
TRANSCRIPT
Page 1
( 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
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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.
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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
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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 •
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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
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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
Page 8
• 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
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