PENTOSE

PHOSPHATE

PATHWAY

Pentose Phosphate Pathway

• Otto Warburg• Frank Dickens

Dr. Bernard L. Horecker

OVERVIEWFunctions1. To generate reducing equivalents, in the form of NADPH, for reductive biosynthesis reactions within cells.2. To provide the cell with ribose-5-phosphate (R5P) for the synthesis of the nucleotides and nucleic acids.3. Although not a significant function of the PPP, it can operate to metabolize dietary pentose sugars derived from the digestion of nucleic acids as well as to rearrange the carbon skeletons of dietary carbohydrates into glycolytic/gluconeogenic intermediates.

Overall Reaction for Stage 1

• 3G6P + 6NADP+ 3H2O -> 6NADPH + 6H+ 3CO2 +3Ru5P

•The reactions of the PPP operate in the cytoplasm.•The pentose phosphate pathway has both an oxidative

and a non-oxidative arm. •The reactions catalyzed by glucose-6-phosphate

dehydrogenase and 6-phosphogluconate dehydrogenase each generate one mole of NADPH each for every mole of glucose-6-phosphate (G6P) that enters the PPP.

•The non-oxidative reactions of the PPP are primarily designed to generate R5P.

•The primary enzymes involved in the non-oxidative steps of the PPP are transaldolase and transketolase

•The net result of the PPP, if not used solely for R5P production, is the oxidation of G6P, a 6 carbon sugar, into a 5 carbon sugar.

Products

NADPHR5P

Intermediates for Glycolysis

Metabolic DisordersRibose-5-phosphate isomerase Deficiency- results to New Inborn Error in the Pentose Phosphate Pathway Associated with a Slowly Progressive LeukoencephalopathyTransaldolase Deficiency- influences the pentose phosphate pathway, mitochondrial homeostasis, and apoptosis signal processing. Glucose-6-phosphate dehydrogenase Deficiency- the MOST COMMON human enzyme defect

Glucose-6-Phosphate Dehydrogenase Deficiency•Characterized by abnormally low levels of G6PD levels•More than 400 different variants of G6PD Deficiency have been identified•G6PD deficiency was discovered as an outgrowth of an investigation of hemolytic anemia occurring in some individuals treated for malaria .•The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to primaquine.•600 million people are affected by this disease•Occurs mainly in Africa, Asia and the Meditteranean•Affects 1 out of 10 African-American males in the US

WORLDWIDE DISTRIBUTION OF G6PD DEFICIENCY

What are the causes of G6PD Deficiency?•G6PD Deficiency is inherited from one or both of your parents. It cannot be passed from one person to another in any other way.

•Males can either be G6PD Deficient or unaffected. Females can be G6PD Deficient, partially deficient (sometimes known as carriers) or unaffected.

Inheritance of G6PD Deficiency

G6PD Deficiency Disorders

HEMOLYTIC ANEMIA- abnormal breakdown of red blood cells (RBCs) either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular).FAVISM- a disorder characterized by hemolytic anemia in response to ingestion of fava beans.CATARACT- a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light.

Favism

AnemiaIn the hexose monophosphate pathway, glucose-6-phosphate dehydrogenase forms most of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) in cells which is necessary for the reactions of various biosynthetic pathways, the stability of catalase and the regeneration of reduced glutathione (GSH) from the oxidised glutathione (GSSG).

The reduced form of NADPH, catalase and GSH are the main antioxidants of cells. In this way glucose-6-phosphate dehydrogenase provides a source of reducing power in the form of sulfhydryl buffers that maintains the integrity of protein and lipid sulfhydryl groups and aids in the detoxification of free radicals and peroxides

In the red blood cells of glucose-6-phosphate dehydrogenase deficient subjects, structural changes will occur during oxidative stress owing to disulphides build up. In turn this causes haemoglobins to denature and precipitate as lumpy particles known as Heinz bodies which attach to the cell membrane and alter its charge, elasticity and permeability.

SYMPTOMS OF ANEMIA •paleness (in darker-skinnedchildren paleness is sometimes best seen in the mouth, especially on the lips or tongue)•extreme tiredness•rapid heartbeat•rapid breathing or shortness of breath•jaundice, or yellowing of the skin and eyes, particularly in newbornsan enlarged spleen•dark, tea-colored urine

• Fava beans are rich in two glycosidic compounds, vicine and convicine

•Upon ingestion, the glycosides are hydrolysed enzymatically to form pyrimidine aglycones, divicine and isouramil respectively.

•The proposed mechanism for the cause of favism is that these new compounds then undergo redox cycling and in the process depleting reduced glutathione (GSH), leading to the formation of free radicals and hydrogen peroxide.

FAVISM

•The idea that cataractogenesis and glucose-6-phosphate dehydrogenase deficiency are linked was first proposed by Zinkham in 1961.

•The cells of the mammalian lens have many properties in common with the red blood cell. This underlines the argument of the importance of glucose-6-phosphate dehydrogenase in maintaining the levels of reduced NADPH available for preventing the oxidation of sulfhydryl (-SH) groups in lenticular cells. In glucose-6-phosphate dehydrogenase deficiency there is a decreased synthesis of ribose and a lower turnover of proteins. Coupled with the low levels of reduced glutathione, this might reduce the solubility of membrane proteins exposed to oxidative stress. Following this, high molecular weight protein (S-S) aggregates are believed to form in the lens and cause cataract development

CATARACTOGENESIS

TREATMENT

•There is no known cure for G6PD Deficiency. It is a lifelong condition• People with G6PD Deficiency may use a list of prohibited food and chemicals to help them prevent severe reactions•Common theme among these food and drug is that all of them are oxidizing agents

Some Prohibited Food and Chemicals for G6PD Deficiency Patients

Foods to be avoided:Fava Beans - Dingdong nuts, Mr. BeanRedwineLegumes - Habitswelas, Garbanzos, Kadyos or Black Beans, MonggoBlueberrySoya Food - Taho, Tofu or Tokwa, Soy SauceTonic WaterBitter Melon or AmpalayaHerbs to be avoided:Cattle gallstone bezoarHoneysuckle flowerChimonanathus flower100% Pearl powderFigwortflowerAcalypha indica

Chemicals to be avoided:Methylene BlueArsinePhenylhydrazineToluidine BlueTrinitrotoluene Aniline Eyes Camphor Napthalene Henna MentholAlaxan Gel Begesic

G6PD Deficiency Advantage•Both the hemizygous G6PD deficient male andhomozygous G6PD deficient female are protected againstfalciparum parasitization.

• Erythrocytes from all G6PD deficient genotypes are relatively protected against falciparum infestation, and that this protection is enhanced by oxidant substances derived from a number of food crops such as fava beans.

WORLDWIDE DISTRIBUTION OF MALARIA

REFERENCES•http://G6pddeficiency.org•http://bloodjournal.hematologylibrary.org/cgi/content/full/111/1/16•http://rialto.com/g6pd/•http://kidshealth.org/parent/general/aches/g6pd.html#•http://teekoonhien.fortunecity.com/g6pdbiochemistry.html•Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homeostasis, and apoptosis signal processing. Y Qian, S Banerjee, CE Grossman, et. Al•Ribose-5-Phosphate Isomerase Deficiency: New Inborn Error in the Pentose Phosphate Pathway Associated with a Slowly Progressive LeukoencephalopathyJojanneke H.J. Huck1, 2, Nanda M. Verhoeven2, et al•G6PD Deficiency as Protection Against falciparum Malaria: An Epidemiologic Critique of Population and xperimental Studies by LAWRENCE S. GREENE

A SWEET QUESTION FROM GROUP 2

HOW MANY SWEETS WERE USED AS THE BACKGROUND PICTURE IN THIS POWERPOINT PRESENTATION? :D