MCB 15: Week 7-2

Created by jordanciuro 

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wht are three central functions of the pentose phosphate pathway

1) NADPH biosynthesis
2)ribose-5-phosphate
3) sugar-phosphate of varying lengths

where is the HMP active?

in tissues that routinely sunthesize fatty acids or steroids

synthesis of 1 palmitoyl-CoA (7 additinos of 2 C units)requires how mjuch NADPH

14

synthesis of 1 cholesterol requires how much NADPH?

14

what form of reducing power does RBC need and why does it need this?

NADPH to protect from ROS

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

transketolases

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

transaldolase

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)

Wernicke-Korsakoff syndrome

mutation reduces affinity for vit b1 in transketolase (TPP)

brain atrophy, amnesia, paralysis

ratio of NADP/NADPH

1:10

vs

nad/nadh ratio= 1000:1

how to make deoxyribonucleosides

reduction of ribonculeosides with NADPH

if this is defected.. NO DNA! WHA!!

what maintains rubonucleotide reductase in proper state?

thioredoxin reductase which requires NADPH

NADPH reducing power usage

indirectly via glutathione from sulfydryl groups of cysteine residues or folate derivatieves. these are ONLY reduced by NADPH

glutathione

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

absorbic acid

vitamin C

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)

Viagra

prolonging NOs action makes this work
done by inhibiting cGMP breakdown

g6p dehydrogenase deficiency

loss of reducing power since you get less NADPH

what are the three primary dangerous radicals

superoxide, hydrogen peroxide, hydroxyl radical

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

superoxide

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)

hydroxyl radical

damages membranes by lipid peroxidation

can damage nucleic acids causing breakage and alter structure of bases

what enzumes detoxify h2o2

catalase, h peroxidase, gsh peroxidase

cofactors for superoxide dismutase

in cytosol: uses Zn and Cu
in mito: uses Mn and Cu

catalase

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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