What is the structural difference between NADH and NADPH?
NADPH has an additional phosphate group at the 2'-position of the ribose linked to adenine that allows enzymes to discriminate between NADH and NADPH (specificity handle)
NADP+ still accepts a pair of electrons & a proton in the nicotinamide ring like NAD+
If the NAD+/NADH ratio in a cell is very high, the NADP+/NADPH ratio in the same cell is:
Very LOW: a cell with a high concentration of NAD+ will therefore also have a high concentration of NADPH
NADPH __ NADP+
NAD+ __ NADH
NADPH is in much higher concentrations than NADP+ (NADPH >> NADP+)
On the other hand, NAD+ is in much higher concentrations than NADH (NAD+ >> NADH)
NADPH provides reducing power for biosynthetic work OUTSIDE the mitochondria
What are the tissues in which the pentose phosphate pathway is most active?
places where NADPH is used:
Liver (coenzyme for drug-metabolizing enzymes)
Adipose tissue (for synthesis of fatty acids/steroids)
adrenal cortex (for steroid hormone synthesis)
erythrocytes (protects from oxidative damage)
phagocytes (as substrate for NADPH oxidase that protects against neutrophil infection via respiratory bursts)
How can the pentose phosphate pathway be manipulated if you're under extreme stress (eg. oxidative attack)?
you'd want to make a lot of NADPH, so the shunt would be run to make NADPH, then the resulting product would be re-converted back into glucose-6-phosphate and the shunt would be run run again until all carbons you started with were exhausted
this is the most extreme form of needing the pathway
How can the pentose phosphate shunt be regulated?
glucose-6-phosphate dehydrogenase is the first committed step AND the rate limiting step (will only proceed if energetically favorable)
insulin induces the pathway
NADPH inhibits the pathway (allosteric feedback)
generates a superoxide anion from oxygen
the generation of reactive oxygen species (ROS) by phagocytes is an important mechanism used to kill engulfed bacteria
What are examples of reactive oxygen species'?
superoxide, hydrogen peroxide & hydroxyl radicals
enzyme that generates hypochlorite (bleach) from hydrogen peroxide and chloride anions during the oxidative burst of a neutrophil
congenital granulomatous disease
defects in forming ROS' (most importantly, the superoxide radical)
can result in the patient being subject to severe recurrent infection + chronic inflammatory conditions due to an inability to kill ingested pathogens
What are some ways reactive oxygen can be harmful? (4)
can cause damage to DNA, especially mtDNA
lipid peroxidation causes increases in permeability that change ion concentration across membranes
it can attack some amino acids and promote cross-linking or fragmentation
they can form in damaged cells/tissues, eg. those recovering from ischemia (problem associated with myocardial infarction, bypass surgery, transplantation)