On page 71 Dr. Moalem describes G6PD as a
"bouncer" that kicks free radicals out of red blood cells. Free
radicals are compounds with incomplete valence shells that can destroy red
blood cells without G6PD. Dr. Moalem
then mentions G6PD deficiency, or favism, is an evolutionary adaptation to
malaria.
Explain the biochemical reaction that requires G6PD to
remove free radicals from hemoglobin. NAPDH plays a role in this reaction; where
have we seen NADPH before, and how is it behaving differently now? Why might antioxidants,
normally associated with good health, increase the severity of malaria in the
body of someone with favism?
This question relates to Big Idea #4 (biological systems
interact and result in complex properties) because G6PD interacts with free
radicals resulting in electron transfer from G6PD to an acceptor, (un)ruptured
hemoglobin, and malaria susceptibility.
Aidan Murphy, amurphy4@students.d125.org
The G6PD, or glucose-6-phosphate dehydrogenase, enzyme mainly plays a role in the 'pentose phosphate' pathway. In this pathway, a glucose molecule is phosphorylated by ATP, transforming the glucose into a more reactive molecule called glucose-6-phosphate. When the G6PD enzyme binds with this molecule, it facilitates the oxidation of glucose-6-phosphate, releasing the necessary electrons to reduce an NADP+ molecule into an NADPH molecule. This NADPH molecule, in turn, gets oxidized and reduces a glutathione disulfide molecule into a glutathione molecule, and it is this glutathione molecule that is the main combative agent in removing free radicals. Glutathione, in its reactive state, has the ability to donate electrons and protons to reactive radicals, neutralizing the danger that they pose to red blood cells. In essence, glutathione serves as the body's natural antioxidant.
ReplyDeleteIn this pathway, NADPH serves as one of the most important molecules in the process, as it is able to reduce and oxidize glutathione molecules, sending them to battle against free radicals as needed. In fact, the ability of NADPH to cycle glutathione is even more important than the concentrations of the glutathione itself, as seen in a study where an increase in glutathione concentrations did not affect oxidative stress, whereas an increase in NADPH did decrease the oxidative stress (http://bloodjournal.hematologylibrary.org/content/77/9/2059.full.pdf).
NADPH has proven to be an essential molecule in the photosynthesis pathways as well; in each pathway, NADPH serves as a reusable battery that reduces and oxidizes molecules as needed, although the specific molecules in each pathway differ. In photosynthesis, NADP+ reduces into NADPH when electrons, produced by a photo-electrically excited pigment, travels through the electron transport chain in the thylakoid membrane. This NADPH is later used to reduce a molecule in the RuBisCO pathway into a G3P molecule, which ultimately turns into glucose.
G6PD deficiency, as described in Survival of the Sickest, has been linked to a decrease in severity of malaria. According to a research article, this may be because radical-damaged erythrocytes get taken out of the blood stream through phagocytosis more quickly than regular erythrocytes, as the immune system recognizes the damaged cell and marks it for destruction by antibodies such as IgG, which has the additional benefit of taking out the malaria-hijacked cell with it (http://bloodjournal.hematologylibrary.org/content/92/7/2527.full). Perhaps antioxidants may serve to reduce the effectiveness of this biological mechanism, as blood cells protected from radicals by antioxidants would not be marked for phagocytosis by antibodies, and thus the malaria-hijacked cell would remain in the blood cells, waiting to wreak havoc in the human body.
(Matthew Zhang, mzhang4@students.d125.org)