Download SUBSTRATE CYCLING (see Voet and Voet)

SUBSTRATE CYCLING (see Voet and Voet)
F6P
F1,6, bisP
Phosphofructokinase I: forward reaction, activated by AMP
fructose 1,6, bisphosphatase: reverse reaction, inhibited by AMP
vf - vr represents cycling: if this difference is small then cycling is large, if difference
is large, cycling is small
eg Muscle
Maximum PFK activity about 10-fold greater than max PBPase activity
Assume under basal conditions that PFK I operates at 10% of maximum and FBPase
operates at 90% of maximum. Also assume that a 4-fold increase in AMP causes PFK to
increase from 10% of max to 90% of max and FBPase to decrease to 10% of maximum.
Assign 100 arbitrary units to full activity of PFK, therefore PBPase equals 10 units
maximum activity
When [AMP] is low: Vf (low) – Vr (high) = 10 – 9 = 1
When [AMP] is high: Vf (high) –Vr(low) = 90 – 1 = 89
Net result effect of an increase in AMP is amplified from about 9-fold to 90-fold.
and a 10% decrease in ATP can result in a 90-fold increase in glycolytic flux as a result
of adenylate kinase and substrate cycling.
Bumble bees: require 30o C temperature in thoracic muscle but can fly at 10o C
Have high levels of FPBase that is not inhibited by ATP leading to cycling and
thermogenesis
Nonshivering thermogenesis: cycling in muscle and liver when it is cold. Stimulated
by thyroid hormone.
Chronic obesity: may be partly related to reduced rate of nonshivering thermogenesis
These individuals tend to be cold sensitive and do not increase rate of thyroid hormone
activation in the cold as normal individuals do.
LACTIC ACIDOSIS
Glycolysis of a glucose molecule effectively results in the generation of 2lactate plus
2H+ (see p 341 in Horton). The plasma membrane contains a transport protein that co-
transports lactate and H+ from the cell into the blood, preventing the intracellular pH
from becoming too low. Excessive glycolysis therefore results in a lowering of blood
pH.
Note also that PFK I is inhibited by hydrogen ions so that a drop in intracellular pH will
lead to a decrease in glycolysis, in effect an example of feed back regulation.
Lactic acid which is transported out of the cell is carried away by the blood.
Normal blood lactic acid concentration is maintained at ~ 1.2 mM or less., but may
increase to greater than 5mM under conditions of lactic acidosis.
When blood flow is inadequate, such as during heavy exercise of skeletal muscle, or an
attack of agina pectoris in the heart, blood flow cannot supply adequate amounts of
oxygen. This results in increased glycolytic activity to provide required ATP and the
rapid production of lactic acid which cannot be removed fast enough. The resulting
build up of hydrogen ions can cause pain.
Tissue hypoxia, with a resulting increase in glycolytic activcity, occurs in all forms of
shock, during convulsions and in deseases involving circulatory and pulminary failure.