Biomedical Education - Metabolism - TCA cycle
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Transcript of Biomedical Education - Metabolism - TCA cycle
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Clinical BiochemistryClinical Biochemistry
BMED19003BMED19003
Lecture 3 and 4 – TCA cycle, electron Lecture 3 and 4 – TCA cycle, electron transport chain and beta-oxidationtransport chain and beta-oxidation
Dr Fiona CoulsonDr Fiona Coulson
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
More metabolism More metabolism –– learning objectives learning objectives
• follow the sequence of carbon molecules from glycolysis to TCA cycle and onto electron transport
• complete the full cycle of ATP production from glycolysis in the presence of oxygen
• understand the importance of NADH and FADH2
• contrast fat breakdown with that of glycolysis
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
EnergyEnergy
Cells need energy to workCells need energy to work
This energy comes from the food we eatThis energy comes from the food we eat
Food is broken down into its component Food is broken down into its component molecules and is absorbed into the portal molecules and is absorbed into the portal bloodstream or lymphaticsbloodstream or lymphatics
What happens after that?What happens after that?
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
What next?What next?
The next step is to either store the food or The next step is to either store the food or use ituse it
We have started talking on how we We have started talking on how we recover energy from carbohydrates recover energy from carbohydrates through the complete oxidation of glucosethrough the complete oxidation of glucose
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Carbohydrate metabolismCarbohydrate metabolism
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Krebs cycle – preparatory stepKrebs cycle – preparatory step
Occurs in the mitochondrial matrix and is Occurs in the mitochondrial matrix and is fueled by pyruvic acid and fatty acidsfueled by pyruvic acid and fatty acids
Pyruvic acid is converted to acetyl CoA in three Pyruvic acid is converted to acetyl CoA in three main steps:main steps:– DecarboxylationDecarboxylation
• Carbon is removed from pyruvic acidCarbon is removed from pyruvic acid
• Carbon dioxideCarbon dioxide is releasedis released
– OxidationOxidation• Hydrogen atoms are removed from pyruvic acidHydrogen atoms are removed from pyruvic acid• NADNAD+ + is reduced to NADH + His reduced to NADH + H++
• Formation of acetyl CoA – the resulting acetic acid is Formation of acetyl CoA – the resulting acetic acid is combined with coenzyme A, a sulfur-containing coenzyme, combined with coenzyme A, a sulfur-containing coenzyme, to form acetyl CoAto form acetyl CoA
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
An eight-step cycle in which each acetic An eight-step cycle in which each acetic acid is decarboxylated and oxidized, acid is decarboxylated and oxidized, generating: generating: – Three molecules of NADH + HThree molecules of NADH + H+ + = 9 ATP= 9 ATP– One molecule of FADHOne molecule of FADH2 2 = 2 ATP= 2 ATP– Two molecules of COTwo molecules of CO22
– One molecule of ATPOne molecule of ATP– total potential of 12 ATPtotal potential of 12 ATP
For each molecule of glucose entering For each molecule of glucose entering glycolysis, two molecules of acetyl CoA glycolysis, two molecules of acetyl CoA enter the Krebs cycleenter the Krebs cycle
Krebs cycleKrebs cycle
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Electron transport chain (ETC)Electron transport chain (ETC)
Food (glucose) is oxidized and the released Food (glucose) is oxidized and the released hydrogens:hydrogens:– Are transported by coenzymes NADH and Are transported by coenzymes NADH and
FADHFADH22
– Enter a chain of proteins bound to metal atoms Enter a chain of proteins bound to metal atoms (cofactors) (cofactors)
– Combine with molecular oxygen to form waterCombine with molecular oxygen to form water– Release energyRelease energy
The energy released is harnessed to attach The energy released is harnessed to attach inorganic phosphate groups (Pinorganic phosphate groups (Pii) to ADP, ) to ADP, making ATP by oxidative phosphorylationmaking ATP by oxidative phosphorylation
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Mechanisms of oxidative phosphorylationMechanisms of oxidative phosphorylation
The hydrogens delivered to the chain are The hydrogens delivered to the chain are split into protons (Hsplit into protons (H++) and electrons) and electrons
– The protons are pumped across the inner The protons are pumped across the inner mitochondrial membrane by:mitochondrial membrane by:• NADH dehydrogenase (FMN, Fe-S)NADH dehydrogenase (FMN, Fe-S)
• Cytochrome b-cCytochrome b-c11
• Cytochrome oxidase (a-aCytochrome oxidase (a-a33))
– The electrons are shuttled from one acceptor The electrons are shuttled from one acceptor to the nextto the next
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Electrons are delivered to oxygen, Electrons are delivered to oxygen, forming oxygen ionsforming oxygen ions
Oxygen ions attract HOxygen ions attract H++ to form water to form water
HH++ pumped to the intermembrane space: pumped to the intermembrane space:– Diffuses back to the matrix via ATP synthase Diffuses back to the matrix via ATP synthase – Releases energy to make ATPReleases energy to make ATP
Mechanisms of oxidative phosphorylationMechanisms of oxidative phosphorylation
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Electric energy gradientElectric energy gradient
The transfer of energy from NADH + HThe transfer of energy from NADH + H++ and FADH and FADH22 to to oxygen releases large amounts of energyoxygen releases large amounts of energy
This energy is released in a stepwise manner through the This energy is released in a stepwise manner through the electron transport chainelectron transport chain
The electrochemical proton gradient across the inner The electrochemical proton gradient across the inner membrane:membrane:– Creates a pH gradient Creates a pH gradient – Generates a voltage gradientGenerates a voltage gradient
These gradients cause HThese gradients cause H++ to flow back into the matrix via to flow back into the matrix via ATP synthaseATP synthase
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
ATP synthaseATP synthase
The enzyme consists of three parts: a rotor, a The enzyme consists of three parts: a rotor, a knob, and a rodknob, and a rod
Current created by HCurrent created by H++ causes the rotor and rod causes the rotor and rod to rotateto rotate
This rotation activates catalytic sites in the This rotation activates catalytic sites in the knob where ADP and Pknob where ADP and Pii are combined to make are combined to make
ATPATP
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Summary of ATP productionSummary of ATP production
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Fate of lipids - vertebrates
Lipoproteins
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Figure 23.1Scanning electron micrograph of an adlpose cell (fat cell). Globules of triacylglycerols occupy most of the volume of such cells.
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Lipid metabolismLipid metabolism Strong links with CHO metabolism through the formation of Strong links with CHO metabolism through the formation of
TCA intermediatesTCA intermediates
Oxidation of lipids provides about 50% of the energy needs Oxidation of lipids provides about 50% of the energy needs of the liver, kidney, heart and skeletal muscle of the liver, kidney, heart and skeletal muscle
Mobilised in response to prolonged exercise, starvation or Mobilised in response to prolonged exercise, starvation or fearfear
Lipases activated within adipocytesLipases activated within adipocytes
Free fatty acids enter bloodstream and combine with Free fatty acids enter bloodstream and combine with albumin albumin
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Lipid metabolismLipid metabolism
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Lipid metabolismLipid metabolism
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
OxidationOxidation of long-chain fatty acids yields energy of long-chain fatty acids yields energy
In mammals, up to ~80% of energy requirements are met In mammals, up to ~80% of energy requirements are met by fatty acid oxidationby fatty acid oxidation
Acetyl-CoA Acetyl-CoA also produced from fatty acids→ oxidised to also produced from fatty acids→ oxidised to COCO22 in the citric acid cycle in the citric acid cycle
Acetyl-CoA Acetyl-CoA important molecule associated with lipid important molecule associated with lipid metabolismmetabolism
Electrons removed from fatty acids (oxidation) are Electrons removed from fatty acids (oxidation) are transferred to the electron transport chain → drives transferred to the electron transport chain → drives synthesis of synthesis of ATPATP
Overview of fatty acid oxidation
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
ββ-oxidation:-oxidation: 4-step process resulting in the 4-step process resulting in the production of C2 acetyl fragment from fatty production of C2 acetyl fragment from fatty acidacid
complete oxidation of fatty acids yields complete oxidation of fatty acids yields COCO22 and H and H22OO
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
-Oxidation of Fatty Acids-Oxidation of Fatty Acids
Repeated sequence of 4 reactions Repeated sequence of 4 reactions
Strategy: 3 reactions to create a carbonyl group Strategy: 3 reactions to create a carbonyl group (C=O)on (C=O)on -C -C
Then fourth reaction cleaves the "Then fourth reaction cleaves the "-keto ester" -keto ester"
Products: (i) Products: (i) acetylacetyl-CoA and (ii) fatty acid two -CoA and (ii) fatty acid two carbons shorter carbons shorter
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Figure 23.6Fatty acids are degraded by repeated cycles of oxidation at the -carbon and cleavage of the CC bond to yield acetate units.
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Acyl-carnitine/carnitine transporter
Fatty acid catabolism occurs inside the mitochondrion – in matrix
Fatty acyl CoA cannot cross the inner membrane, so fatty acyl group is transferred to carnitine (carnitine can cross the membrane)
Assisted by specific carnitine carrier protein
© 2003 By Default!Dr Fiona Coulson– Biomedical Sciences, CQU BMED19003 Lecture 3&4 – Metabolism
Summary of Summary of -Oxidation-Oxidation
Repetition of the cycle yields a succession of Repetition of the cycle yields a succession of acetateacetate units units
Thus, palmitic acid (C16) yields eight acetyl-Thus, palmitic acid (C16) yields eight acetyl-CoAs (to TCA cycle – oxidation to COCoAs (to TCA cycle – oxidation to CO22 & H & H22O)O)
Complete Complete -oxidation of one palmitic acid yields -oxidation of one palmitic acid yields 106 molecules of ATP 106 molecules of ATP
Large energy yield is consequence of the Large energy yield is consequence of the highly highly reduced state of fatty acids reduced state of fatty acids (….[CH2](….[CH2]nn….)….)
This makes fatty acids the fuel of choice for This makes fatty acids the fuel of choice for migratory birds, animals (hibernation/famine/etc)migratory birds, animals (hibernation/famine/etc)