Bioenergetics and Oxygen Toxicity in Cardiovascular System 2014
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BIOENERGETICS AND OXYGEN TOXICITYIN CARDIOVASCULAR SYSTEM
Rondang R. Soegianto2014
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Terminology: Bioenergetics Energy trransduction Biochemical thermodynamics Central theme: Understanding the mechanism of ATP synthesis through the oxidation of substrates (Nicholls) Specificity: Describes the transfer and utilization
of energy in biologic systems (Lippincott)
I. Bioenergetics
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G = H - TS
T = absolute temperatureH = enthalpy, heatS = degree of organization of atoms involved in reaction
G = available useful energy
Gibbs free energy (G) and Gibbs change of free energy (G)
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In the human body, T is constantThus:
H (enthalpy) changes are negligible and principally associated with
chemical bonds known as Internal Energy (Chemical Energy).Meaning: H = G Hence: G = E - TS (Lange, Exam. & Board Review)
Note: Nonbiologic systems utilize heat energy to
perform work. Biologic systems are isothermic and utilize chemical energy for living processes.
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Sign of G predicts the direction of a reaction
G = negative: Reaction is exergonic Proceeds with net loss of free energy Reaction goes spontaneously G = positive: Reaction is endergonic Proceeds only with net gain of energy
G = zero: Sistem is at equilibrium No net change takes place
Exothermic and endothermic reactions involve H as variable.
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Coupling of Endergonic to Exergonic ProcessesHarper 21st, Fig. 11.1
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Transfer of Energy via a High-energy Intermediate Compound Harper 21st, Fig 11-3
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Transduction of energy through ........Harper 21st, Fig 11-4
Transduction of energy thru common high-E comp.
Harper 21st, Fig 11-4
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Devlin 5th, p 538, Fig 13.1
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High-energy phosphates are involved in coupling processes
Harper 26th, p 82
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ATP = energy currency of the cell
Other nucleoside triphosphates: UTP, GTP, CTPMay take part in phosphorylations in the cell transferring free energy.
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II. Biologic Oxidation
- Oxidation processes in living systems - Catalyzed by class I enzymes: Oxidoreductases
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Definition: Oxidation = Loss of electrons
Reduction = Gain of electrons Oxidation-reduction (redox) reactions are reversible
A ox + B red A red + B ox
Fe2+ Fe3+ + e-
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Oxidoreductases (Harper 26th)
1. Oxidases: A Containing Cu B As flavoproteins
2. Dehydrogenases: A. NAD+ or NADP+ as coenzyme B Flavin as coenzyme C Cytochromes (Fe-porphyrin as coenzyme)
3. Hydroperoxidases: A Peroxidase B Catalase 4. Oxygenases: A Dioxigenase B Monooxigenase
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1. Oxidases: - Remove 2 protons (H+) from substrate and pass to oksigen - Generate H2O or H2O2 Two groups of oxidases: A Containing Cu Example: Cytochrome a3 (cyt a3) also known as cyt aa3 Is a cytochrome oxidase Terminal compound of the respiratory chain in
mitochondria B. Flavoproteins, contain FMN or FAD Ex. : L-aminoacid oxidase Xanthine oxidase Aldehyde dehydrogenase
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2. Dehydrogenases cannot use O2 as H or e- acceptor
A. NAD+ or NADP+ as coenzyme Generally: NAD+-linked dehydrogenase in
energy transduction reaction
NADP+-linked (as NADPH) dehydrogenase in reductive synthesis
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B. Flavin as coenzyme Tightly bound to apoenzyme (prosthetic group) Linked to e- transport of the respiratory chain
C. Cytochromes Fe-containing hemoproteins
In the resp. chain: cyt b, c1, c, a (and cyt a3 which is an oxidase)
Cyt also in endoplasmic reticulum (P450 and P5), in plant cells, bacteria and yeast.
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3. Hydroperoxidases use H2O2 as substrate
A. Peroxidase reduces peroxides using various e- acceptors
H2O2 + AH2 2 H2O + A
In erythrocytes and other tissues:
H2O2 + 2 GSH GSSG + H2O GSH = Reduced gluthatione Glutamyl-cysteinyl-glycine (a tripeptide) -SH = Reducing group of cysteine residue
Peroxidase
Gluthatione peroxidase
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B. CatalaseHemoprotein with 4 heme groups
2 H2O2 2 H2O + O2
Found in: Blood, bone marrow, mucous membranes Kidney, liver Catalase destroys peroxides formed by oxidases
Catalase
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4. OxygenasesCatalyze direct transfer & incorporation of oxygen into asubstrate molecule. A. Dioxygenases Incorporate both atoms of molecular oxygen into the
substrate.
A + O2 AO2
Example: Homogentisate dioxygenase (oxidase)
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B. Monooxygenases (Mixed-Function Oxidases, Hydroxylases) Incorporate only one O atom into substrate. The other O atom is reduced to water.
AH + O2 ZH2 AOH + H2O + Z
Examples: Detoxication of many drugs Hydroxylation of steroids
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Free radicals
Transfer of a single e to O O (superoxide anion)Can damage membranes, DNA, etc.
Destructive effects Amplified by: Free radical chain reaction Removed by: Superoxide dismutase (SOD) in the reactions
O + O 2H H O + O
H O 2H O + O Catalase22 2
-
2
-
2
+
2 2SOD
2 2
2
-2 2
-
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Mitochondria Make > 90% of cellular ATP
“Powerplant” of the cell Four Compartments
Matrix has numerous enzymes that reduce NAD+ to NADH during catabolism of “foodstuffs”
Inner Membrane has: Proteins that transfer electrons (the ETS) ATP synthase
Intermembrane SpaceOuter Membrane
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Faces of mitochondrial membrane (V & V Fig. 20-3)
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Role of RC of mitochondria in the conversion of food energy to ATPHarper 26 Fig. 12-2
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Harper 26 Fig. 12-4
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Cardiac muscle has high ATP demand.
Higher content of mitochondria than mosttissues.
High content of Electron Transport Chainproteins: ATP synthase, ATP-ADP translocase, TCA cycle.
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Also:
High content of creatine kinase as energybuffer and energy shuttle (as well as brain) Heart (and brain) sensitive to ischemia andanoxia decreased ATP production
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Consequence of decreased ATP:
- Ion influx (Na+, Ca2+)- Swelling of tissue
Cardiac mitochondria can sequester Ca2+
Effect:Low amt stimulates TCAHigh amt activates phopholipase degrades membrane lipids
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Cardiovascular system is subjected to oxidative stress and injury caused by: Reactive Oxygen Species (ROS) O2
.- = Superoxide radical H2O2 = Hydrogen peroxide OH. = Hydroxyl radical (most potent to attack DNA and membrane)
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Environmental stressors: - Radiation- Air pollutants (ozone, SO2, acid rain)- Herbicides
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Defenses against oxidants: A. Enzymes:
- SOD (Mn SOD in mitoch., Cu Zn SOD in cytosole) - Catalase - Glutathione peroxidase
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Extracellular fluid (blood plasma) is Poor in antioxidant enzymes Cu Zn SOD which is bound to surface of endothelial cells = extracellular SOD, distinct from intracellular, cytosolic Cu Zn SOD
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B. Small molecule antioxidant in plasma: - Ascorbic acid - α Tocopherol - Carotenoid - Endproducts of metabolic pathways, bilirubin, uric acid
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Different ways of antioxidant action. Small molecules antioxidants act by directly scavenging oxidants and will be consumed during action. In contrast, antioxidant enzymes act catalytically, thus can be reused.
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REFERENCES: Harper’s Illustrated Biochemistry 27th Ed. Lange medical book, 2006 Molecular Biology of Free Radical Scavenging System. Current Communications. J. G. Scandalios, Editor. 1992 Marks’Basic Medical Biochemistry. A Clinical Approach. Third Edition. 2009