1 - University of Arizona
1. PENTOSE PHOSPHATE PATHWAY
- source of NADPH for reductive synthesis of fatty acids and cholesterol in liver, kidney, and adipose
- NADPH maintains glutathione in reduced state
- can also provide source of ribose-5-phosphate ( nucleotide synthesis ( nucleic acids
- provides for interconversion of pentoses with hexoses/trioses
Oxidative branch (irreversible)
- glucose-6-P ( 6-Phosphogluconate ( Ribulose-5-Phosphate (Ribose-5-phosphate)
- key enzyme and rate-limiting step is glucose-6-P dehydrogenase; produces first of two NADPH, used NADP+ as cofactor; glucose-6-PDHase has regulation ( feed back inhibition by NADPH
- second molecule of NADPH produces in oxidative branch is product of 6-phosphogluconate dehydrogenase ( catalyzes decarboxylation of hexose to a pentose sugar (ribulose-5-P)
- end product is ribose-5-P ( precursor for synthesis of nucleic acids
Non-oxidative branch (reversible)
- includes sugar intermediates containing 4,5, or 7 carbons
- transketolase ( catalyzes 2/3 of reaction in branch; requires thiamine diphosphate (TDP)as a cofactor (prosthetic group) as well as Mg2+ ions (as does PDH and alpha-ketoglutarate dehydrogenase)
-thiamine (B1) deficiency affects both ribose-5-P production for nucleic acid synthesis and energy metabolism for carbohydrates; Wernicke-Korsakoff syndrome exhibits memory loss due decreased synthesis of nucleic acids in nervous tissue
- high carb diet ( thiamine deficiency ( beriberi; tiring, weakness related to energy depletion; high carb diet ( individuals rely on pyruvate and alpha-ketoglutarate DHase for aerobic production of ATP from glucose
- when non-oxidative branch begins with ribulose-5-P ( endproducts are glycolytic intermediates: glyceraldehyde-3-P and fructose-6-P; reversible reactions starting with these intermediates ( ending with ribose-5-P
Cellular needs for ribose-5-P and NADPH
- cell requires NADPH but not ribose-5-P
- glucose-6-P from hexokinase in most tissues, but by glucokinase in liver/pancreatic beta-cells ( oxidative branch to ribulose-5-P ( converted to fructose-6-P and glyceraldehyde-3-P in 2:1 ratio ( intermediates can be metabolized to pyruvate in glycolysis or returned to glucose-6-P via gluconeogenic pathway
- shunting around part of glycolysis (hexose monophosphate shunt)
- 2/3 of ribulose-5-P must be used to form xylulose-5-P with remaining 1/3 being converted to ribose-5-P
- both oxidative and non-oxidative branches working
Cell requires ribose-5-P for nucleic acid synthesis but does not require NADPH
- fructose-6-P and glyceraldehyde-3-P provided from glycolysis in 2:1 ratio for non-oxidative branch
- non-oxidative branch proceeds in opposite direction than figure 1
- ribose-5-P produced from glycolytic intermediates; oxidative pathway shutdown by NADPH feedback inhibition
Cell requires both NADPH and ribose-5-P
- cell operates only oxidative branch of pentose pathway
- all ribulose-5-P converted to ribose-5-P
2. REACTIVE OXYGEN SPECIES (ROS)
- toxic ROS generated during normal course of cellular metabolism; ROS inhibited through action of antioxidants
- look at table for ROS and antioxidants that reduce them (14-4)
Free radicals
- unpaired electron; extremely reactive against compounds that contain double bonds like unsaturated lipid (plasma membrane) and nucleic acids bases
- when damage occurs to membranes ( oxidized molecules recycled
- antioxidants eliminate ROS before they cause damage
Singlet oxygen – generated from molecular oxygen in presence of UV light and heme iron; found in skin; not a radical; reacts with biological molecules and generates oxygen radicals (superoxide); contributes to oxidative damage in cells
Superoxide radical anion- superoxide; formed by transfer of a single electron to oxygen; accomplished via coenzyme Q in mitochondrial electron transport chain or by NADPH oxidase in WBCs
Hydrogen peroxyl radical – produced by protonation of superoxide; participate in same reactions as hydroxyl radicals (less reactive)
Hydrogen peroxide – central role in formation of ROS; produced from superoxide via superoxide dismutase (antioxidant) and Haber-Weiss reaction
Hydroxyl radical – most reactive ROS; produced from superoxide via Haber-Weiss reaction or via spontaneous degradation of hydrogen peroxide catalyzed by free metal ions such as iron; basis for antibiotic actions of hydrogen peroxide
Lipid peroxyl radical – depends on action of hydroxyl radicals; primary targets of hydroxyl radicals are membrane phospholipids because most fatty acids in these structures are unsaturated (double bonds) ( reaction forms a lipid radical intermediate ( rapidly oxidized by molecular oxygen to form lipid peroxyl radical ( further oxidizes membrane lipids ( regenerates more hydroxyl radicals
3. ANTIOXIDANT DEFENSE
Glutathione and selenium
Glutathione peroxidase: 2 GSH + H2O2 ( GSSG + 2 H2O
- glutathione, a tripeptide (glu-cys-gly), exists predominantly in reduced form (GSH) when cys has free SH group
- oxidized form (GSSG) consists of two tripeptides linked by a disulfide bond (-S-S-)
- GSH oxidized to GSSG via glutathione peroxidase (uses hydrogen peroxide)
- reduced glutathione (2 GSH) is a natural antioxidant
- selenium required for activity; cysteine residue is active site modified to selenocysteine
- GSH/GSSG = 100:1
Glutathione reductase: GSSG + NADPH + H+ ( 2 GSH + NADP+
- reductase contains bound FAD to transfer electrons from NADPH to GSSG
- NADPH derived from pentose pathway (niacin is precursor of NADPH)
Glutathione and pentose phosphate pathway
- defect in glucose-6-PDHase in RBC ( defects in membrane stability
- event that demands RBC for NADPH increase ( defect in G6DPH prevents cell from maintaining adequate amount of GSH to reduce peroxides
- peroxides in blood can convert hemoglobin ( methemoglobin and destroy RBC membrane through oxidation of phospholipids ( RBC destruction ( rise in insoluble bilirubin in blood
- bilirubin is a breakdown product of heme that is insoluble until processed by liver into a soluble form
Catalase and superoxide dismutase
- catalase: 2 H2O2 ( H2O + O2
- hydrogen peroxide catalytically removed by catalase
- catalase contains four heme groups; enzyme found in liver, kidney, blood, and mucous membranes
- often localized in peroxisomes of cell
- hydrogen peroxide produced by catabolism of superoxide by superoxide dismutase that catalyzes reaction of 2O2-. + 2H+ ( H2O2 + O2
- superoxide dismutase in cytoplasm contains two identical subunits requiring Cu2+ and Zn2+ as cofactors; mitochondrial enzyme requires Mn2+ as a cofactor
- although ROS hydrogen peroxide is form ( it is easily reduce to water by catalase
- mutants in Cu,Zn-superoxide dismutase gene occurs in patients with familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder
Antioxidant cascade
Glutathione – reduced glutathione (GSH) protects cell against peroxides (glutathione peroxidase) and then is regenerated ultimately by NADPH produced in pentose phosphate pathway
Vitamin C –
- GSH plays an additional antioxidant role through its ability to regenerate reduced vitamin C (ascorbic acid) ( protects cells against oxidant effects of both hydroxyl radicals and superoxide radical anion by reducing them
- reduced vitamin C restores vitamin E to its reduced state
- vitamin C maintains iron in reduced state (in prolyl and lysyl hydroxylase) of collagen synthesis
- deficiency ( scurvy
- excess vitamin C intake ( production of oxalates ( formation of kidney stones as calcium oxalate
Vitamin E
- antioxidant role of reduced Vitamin E is to rid cell of lipid peroxyl radical; it also acts on singlet oxygen and peroxyl free radical
- vitamin E is a fat-soluble vitamin; its major constituent is alpha-tocopherol
- vitamin E deficiency (rare) leads to increased peroxidation of membrane lipids, decreased mitochondrial activity, DNA mutations, and damage to cell transport processes; fragility of RBCs
................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related download
- the university of arizona and clark university
- energy ecology evolutionary biology
- chapter one university of arizona
- table of contents university of arizona
- saguaro life history ecology evolutionary biology
- 1 university of arizona
- copper sulfate is an algicide that university of arizona
- low t alteration of volcanoplutonic arc rocks
- anth 235 trade exchange power david soren
Related searches
- university of arizona salaries
- university of arizona salary list
- university of arizona salary 2018
- university of arizona financial
- university of arizona address tucson
- university of arizona admissions status
- university of arizona application 2020
- university of arizona arthritis center
- university of arizona rheumatology
- university of arizona body donation
- university of arizona employment
- university of arizona salary grades