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Substrate cycling


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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.
 


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