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TISCHLER LECTURE 25
OXIDATIVE PHOSPHORYLATION:
AN EXPLOSION OF ENERGY
1.
What effect does insulin have on glucose transport increases by moving transporters to the membrane
Quiz 8
2. Name one tissue where insulin controls glucose transport muscle OR adipose. 3. Glucose increases insulin secretion by causing an increase in the cell concentration of what molecule? Calcium 4. What vitamin is the precursor for NADH? Niacin 5. How is pyruvate kinase structurally modified after glucagon binds to the liver cell? Phosphorylation 6. In the red cell, which lacks mitochondria, how is NAD for glycolysis replenished to keep glycolysis going? Conversion to lactate or LDH 7. Identify an allosteric inhibitor of the phosphofructokinase -1 reaction. ATP or citrate or H+ 8. Identify an allosteric activator of the phosphofructokinase -1 reaction. AMP or fructose-2,6-bisphosphate
2
OBJECTIVES
1. Distinguish between electroneutral and electrogenic transport; describe the significance of electrogenic transport for the adenine nucleotide transporter and the role of this transporter. 2. Discuss oxidative phosphorylation in relation to the chemiosmotic model. 3. Identify the components of the ATP synthase complex, and describe their roles. 4. Explain how the malate-aspartate and the -glycerol phosphate electron shuttles generate energy from the NADH produced by glycolysis. (Do not memorize the layout of the shuttle to reproduce it but understand their key aspects) 5. Define respiratory control and uncoupling, and describe the physiological importance of these processes.
PHYSIOLOGICAL PREMISE Why do some snake and spider venoms cause cell death at the site of the bite in particular? Some of these venoms contain enzymes called phospholipases. Phospholipases hydrolyze membrane phospholipids to release fatty acids. Phospholipases in snake or spider venom degrade phospholipids in the mitochondrial membrane. The fatty acids released act as natural uncouplers that, as is described in this lecture, prevent oxidative phosphorylation by destroying the pH gradient. Consequently the cell dies because of an inability to produce enough energy.
MITOCHONDRIAL TRANSPORT SYSTEMS Examples of Electroneutral Transport: Pyruvate1- moves into matrix and OH1- moves out Phosphate1- moves into matrix and OH1- moves out
MITOCHONDRIAL TRANSPORT SYSTEMS Inner Intermembrane Membrane Space Matrix Side ATP4ADP3Net negative charge moves out
Electrogenic Transport
Glu1- + H+
Asp1-
Aspartate translocase
INTERMEMBRANE SPACE 4H+ complex I NADH FMNH2 + H+4H+ eeeinner e membrane NAD+ CoQ complex III + 4H 2H e cyt b e2H+ C1 O2 e cyt e-H O e a-a3 -C 2 e 4H+ complex IV
OH-
ATP43ADP ADP3-
ATP4-
Pi
3ADP3-
3H+
ATP4-
F1
MATRIX
stalk
Fo
Proton gradient/ Charge gradient 3H+
OAA (6)
Glu0 Asp-1 KG
(5)
Asp-1
(4)
(3) eMalate NAD+ MATRIX
KG (2)
eMalate CYTOPLASM
e = electrons CYTOPLASM Glucose GLYCOLYSIS NAD+ Pyruvate Dihydroxyacetone phosphate (DHAP) (1) Glycerol 3-phosphate OUTER MEMBRANE
O2
e CoQ e FADH2
INNER MEMBRANE
MATRIX
NADH e NAD+
e Glycerol-3-phosphate dehydrogenase
FAD
Figure 4. Glycerol phosphate shuttle. Cytoplasmic glycerol 3phosphate dehydrogenase (1) oxidizes NADH. Glycerol 3-phosphate dehydrogenase in the inner membrane (2) reduces FAD to FADH2.
RESPIRATORY CONTROL depends on the availability of ADP increased ADP in matrix opens proton channel
UNCOUPLER EFFECTS hydrophobic molecules that bind protons take protons into matrix to collapse pH gradient without pH gradient, synthesis of ATP ceases electron transport chain operates at high rate; protons are pumped out rapidly in attempt to restore pH gradient energy is released as heat and the body temperature rises respiratory control is lost uncoupled brown fat mitochondria generates body heat in infants until shivering reflex develops
LACTATE
GLYCOGEN
NADH
GLUCOSE
NADH
CYTOPLASM
ALANINE
complex IV
Mal
H+
ICDH
KgDH
MITOCHONDRIAL MATRIX
complex III
NAD ADP + Pi
complex I
H+
ATP
X
uncoupler
H+ ATP
ADP
Pi
Medical Scenario I: As a current medical student and a former lawyer you become interested in what could have been a lucrative malpractice case in the 1920's. At that time, some physicians, without the benefit of modern biochemistry knowledge, prescribed dinitrophenol as a weight-reducing agent. For some patients it worked satisfactorily, the only side effects being sweating and a slight elevation in temperature. However, in patients who were more overweight and required long-term treatments, their body temperature increased to such an extent that death resulted. Associated with their condition was a marked increase in their rate of respiration and an inability to gain weight even with increased caloric intake. Medical Scenario II:
During World War II workers in munitions factories were exposed to a chemical called trinitrophenol. A common occurrence in these workers was frequent absenteeism due to elevated temperature, weakness and accelerated breathing that improved after several days at home. What would you have recommended to reduce the incidence of such illness?