BIOENERGETICS AND OXYGEN TOXICITY

IN CARDIOVASCULAR SYSTEM

Rondang R. Soegianto
2014
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I. Bioenergetics
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)
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Gibbs free energy (G) and Gibbs change of free energy (G)

G = H - TS
T = absolute temperature
H = enthalpy, heat
S = degree of organization of atoms involved in
reaction
G = available useful energy

In the human body, T is constant

Thus:
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

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

Coupling of Endergonic to Exergonic Processes

Harper 21st, Fig. 11.1

Transfer of Energy via a High-energy Intermediate Compound

Harper 21st, Fig 11-3

Transduction
of energyof
through
........
Transduction
energy
thru common high-E comp.
Harper 21st, Fig 11-4

Harper 21st, Fig 11-4

Devlin 5th, p 538, Fig 13.1

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, CTP
May take part in phosphorylations in the
cell transferring free energy.

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II.- Oxidation
Biologic
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
Fe2+

A red + B ox

Fe3+ + e13

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)

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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 eacceptor

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
Linked to e- transport of the respiratory

group)
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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Peroxidase

3.

Hydroperoxidases use H2O2 as substrate

A. Peroxidase reduces peroxides using various eacceptors Gluthatione peroxidase
H2O2 + AH2

2 H 2O + A

In erythrocytes and other tissues:

H2O2 + 2 GSH

GSSG + H2O

GSH = Reduced gluthatione

Glutamyl-cysteinyl-glycine (a tripeptide)

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B.

Catalase

Catalase
Hemoprotein with 4 heme groups
2 H2 O 2

2 H2O + O2

Found in: Blood, bone marrow, mucous

membranes
Kidney, liver
Catalase destroys peroxides formed by oxidases
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4.

Oxygenases
Catalyze direct transfer & incorporation of oxygen into a
substrate 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
- O
Transfer of a single e to
O - (superoxide anion)
2
2
Can damage membranes, DNA,
etc.

Destructive effects
Amplified by: Free radical chain reaction
Removed by: Superoxide dismutase (SOD) in the reactions
O

+ O -2H

SOD

H O

H O
2

Catalase
2

+ O
2

2H O + O
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 Space
Outer 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 ATP

Harper 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 most
tissues.
High content of Electron Transport Chain
proteins: ATP synthase,
ATP-ADP translocase, TCA cycle.

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Also:
High content of creatine kinase as energy
buffer and energy shuttle (as well as brain)
Heart (and brain) sensitive to ischemia and
anoxia decreased ATP production

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Consequence of decreased ATP:

- Ion influx (Na+, Ca2+)
- Swelling of tissue
Cardiac mitochondria can sequester Ca 2+
Effect:
Low amt stimulates TCA
High 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
- 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:
Harpers Illustrated Biochemistry 27th Ed.
Lange medical book, 2006
Molecular Biology of Free Radical
Scavenging
System. Current Communications.
J. G. Scandalios, Editor. 1992
MarksBasic Medical Biochemistry. A Clinical
Approach. Third Edition. 2009
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