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wht are three central functions of the pentose phosphate pathway
1) NADPH biosynthesis
3) sugar-phosphate of varying lengths
hwo is hemoglobins Fe maintained in proper +2 configuration
methemoglobin reductase which uses NADH NOT NADPH
what is the main regulatory step in HMP
glucose6phosphate to 6p-gluconolactone.
this step is inhibited by NADPH
transfer 2 carbon keto groups. they also require thiamin pyrophosphate (TPP) covalently bound to enyme via schiff base to the nh2 group of lysine residue
creates 4 and 6 c sugar from 7 and 3 sugar. this does not require TPP and transfers a 3 c fragment
fates of ribulose-5-phosphate
1)epimerization to xylulose 5 p
2)isomerization to ribose 5 p (nucleotides)
remaining xlulose5p can be reset by transketolase to sedoheptulose 7 p (7C)
mutation reduces affinity for vit b1 in transketolase (TPP)
brain atrophy, amnesia, paralysis
how to make deoxyribonucleosides
reduction of ribonculeosides with NADPH
if this is defected.. NO DNA! WHA!!
NADPH reducing power usage
indirectly via glutathione from sulfydryl groups of cysteine residues or folate derivatieves. these are ONLY reduced by NADPH
major defense against oxidative stress. -SH groups sacrificed so that other essential proteins are in the reduced state.
it comes from non-ribosomal hepatic origin
what happens if glutathione cant protect -SH groups on proteins from being oxidized?
then globular proteins will lose ther 3 primed structure. this formes masses " HEINZ BODIES". this makes cells less pliable, RBC removal, and hemolysis of spleen
glutathione's role in reducing peroxides?
glutathione peroxidase requires Se as cofactor and reduces hydrogen peroxide to peroxide and water.
this reduces organiz peroxides to alcohols, and reverses lipid peroxidation
BUT if you have selenium deficiency- you are very likely to get damage by ROS
how does liver use glutathione-s-transferase
it attaches glutathione to toxic molcules which makes them more solule (resembles p450)
detoxificiation of acetaminophen (tylenol)
broken down first by cytochrome p450 enzyme which forms highly toxic intermediate NAPQI. BUT glutathione's action now creates that into a non-toxic product that is secreted
however, in an overdose. glutathione reserves are exhausted so buildup of NAPQI results in liver damage
MAYBE N-acetyl-cystein (precursor to GSH) can protect against NAPQIs effects
when it is oxidized it turns into dehydroazcorbate which is recyceld by takign Hs from reduced glutathione which is recycled by NADPH from shunt
NADPH involvement in cytochrome p450
cytochrome p450 is nadph dependent mono-oxygenase. it requires NADPH in HYDROXYLATIONS of aromatic and aliphatic compounds (usually in eukaryotic ER, not mitocondria)
ex xenobiotics- after hydroxylation, they become more hydrophilic and easily excreted via urine
exception=tobacco smoke and aflatoxin become MORE DANGErous!
role of NO
formed by NADPH through reduction of l-arginine
indirectly an endogenous vasodilator
forms radical OH and mediates bacteriocidal activity
inhibits platelet aggregation so interferes with thrombus initiation
how do you form NO
from L-arginine and NADPH
NO synthase (CA DEPENDENT ENZYME)
side effects: NO diffuses to smooth muscles where it synthesizes cGMP which makes muscles contract
(conversion of cGMP- 5 GMP is done by guanylate phosphodiesterase)
antioxidants other than NAPDH
fat soluble: Vit A, Vit E(alpha-tocopherol, lycopenes)
water soluble: vitamine C, Glutathione
Uric Acid (gout patients rarely get MS)
Bilirubin- against lipid peroxidation
normal by product of oxidative metabolism at the level of CoQ
it is relatively non-toxic but when its radicals join with NO it forms dangerous peroxynitrate (OONO). this can cause peroxidation and nitration of tyrosyl hydroxide groups in proteins which is bad
Amyotrophic lateral sclerosis (Lou Gehrig's disease aka maladie de Charcot)
neurodegenerative: motor neurs affected
enzyme defect: cytosolic superoxide dismutase (inability to detoxify O2)
damages membranes by lipid peroxidation
can damage nucleic acids causing breakage and alter structure of bases
contains Heme and Fe
in peroxisomes which is filled with hydrogen peroxides
1/4th of our alcohol is broken down in peroxisomes in this way (alcohol dehydrogenase)
superoxide/peroxide is not always bad- when is it useful?
phagocytes/macrophages: need it to destroy bacteria ect through a respiratory burst
htis uses rapid glucose metabolism by pentose shunt to produce NADPH ( respiratory burst uses NADPH oxidase to make NADPH turn into NADP) this helps o2 turn into o2- which goes into h2o2 then oh which is the killer (uses Fe+2 to Fe +3)
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