HMP Pathway- A Quick Revision

HMP Pathway- A Quick Revision

Namrata ChhabraSSR Medical College,

Mauritius

05/02/2023Namrata Chhabra, M.D. 2

HMP Pathway

Phospho gluconate pathwayPentose phosphate pathway Hexose monophosphate shunt [HMP shunt]All the intermediates of this pathway are in the mono phosphate

form contrary to glycolysis where bisphosphate forms of intermediates are also there.


What is the purpose of HMP pathway ?

• An alternative route for the metabolism of glucose• What is the outcome ???oNADPHo PentosesoNot directly meant for energy production.


Where does this pathway take place ?

Organs/TissuesRapidly dividing cells and in tissues where there is a great requirement of NADPH such as: Liver, Adipose tissue, Adrenal cortex, Gonads Lens, RBCs and Lactating mammary gland

The pathway is less active in the skeletal muscle.


HMP Pathway

• All the reactions of this pathway take place in the cytoplasm


An overview

HMP Pathway

Oxidative phase

NADPH Pentoses

Non –Oxidative PhaseGlycolytic intermediates


Oxidative phase leads to formation of Ribose-5-P by oxidative decarboxylation

Non oxidative phase involves rearrangement process results in the formation of glycolytic intermediates


Glycolysis V/S HMP pathwayCharacteristics

Glycolysis HMP pathway

Occurrence All cells of the body Active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary glands.

Coenzyme NAD + NADP+

CO2 production No CO2 production CO2 is produced.

Pentose production

Pentoses are not produced

Pentoses are produced.

Intermediates Intermediates can be in the mono or bisphosphate forms

Intermediates are never in the bisphosphate form.

Energy ATP is utilized as well as produced

ATP is neither utilized nor produced.Glycolytic intermediates may enter glycolytic pathway to produce energy

Biological Significance

Energy production both in aerobic and anaerobic conditions

NADPH is required for reductive biosynthesis and Pentoses are required for synthesis of coenzymes and nucleotides.


Reactions of HMP pathway- Oxidative phase

Reactions of oxidative phase of HMP pathway- 2 molecules of NADPH and one of CO2 are produced in the oxidative phase.


Reactions of HMP pathway- Non-

Oxidative phase• Ribulose 5-phosphate 3-

epimerase (Phosphopentose epimerase) alters the configuration about carbon 3, forming the epimer Xylulose 5-phosphate, also a ketopentose.

• Ribose 5-phosphate keto Isomerase (Phosphopentose isomerase) converts Ribulose 5-phosphate to the corresponding aldopentose, ribose 5-phosphate.


Non-oxidative phase• The pathway catalyzes the interconversion of :• three, • four, • five, • six, and seven-carbon sugars in a series of nonoxidative reactions• that can result in the synthesis of o five-carbon sugars for nucleotide biosynthesis or o the degradation of excess five-carbon sugars into intermediates of the

glycolytic pathway.


Rearrangement of sugars in the Non-oxidative phase


Step-1-Non-oxidative phase

• Transketolase catalyzes the transfer of the two-carbon unit comprising carbons 1 and 2 of a ketose (from Xylulose 5-phosphate) to the aldehyde carbon of an aldose sugar (ribose 5-phosphate), producing the seven-carbon ketose sedoheptulose 7-phosphate and the aldose glyceraldehyde 3-phosphate.


Step-1- Non-Oxidative phase• Transketolase effects the conversion of a ketose sugar

into an aldose with two carbons less and an aldose sugar into a ketose with two carbons more.

• The reaction requires Mg2+ and thiamine pyrophosphate (vitamin B1) as coenzyme.

• Clinical significance- R.B.C Transketolase activity is measured to diagnose underlying thiamine deficiency.

• In thiamine deficiency Transketolase activity is reduced.


Step-2- Non-Oxidative phase• Transaldolase catalyzes

the transfer of a three-carbon Dihydroxyacetone moiety (carbons 1–3) from the ketose sedoheptulose -7-phosphate onto the aldose glyceraldehyde 3-phosphate to form the ketose fructose 6-phosphate and the four-carbon aldose Erythrose 4-phosphate


Step-3 Non-Oxidative phase

• In this reaction catalyzed by transketolase, Xylulose 5-phosphate again serves as a donor of glycoaldehyde.

• In this case Erythrose 4-phosphate is the acceptor, and the products of the reaction are fructose 6-phosphate and glyceraldehyde 3-phosphate.


Biological advantage of reversible reactions

• Since the reactions of non oxidative phase are irreversible, the glycolytic intermediates can also rearrange to form pentoses.

• The sum of these reactions is:


Degradation of excess Pentoses through HMP pathway

• Xylulose 5-phosphate can be formed from ribose 5-phosphate, or vice versa, by the sequential action of phosphopentose isomerase and phosphopentose Epimerase, therefore:

o Thus, excess ribose 5-phosphate formed by the pentose phosphate pathway can be completely converted into glycolytic intermediates.

o Moreover, any ribose ingested in the diet can be processed into glycolytic intermediates by this pathway.

o The carbon skeletons of sugars can be extensively rearranged to meet physiologic needs.


Summary


Complete oxidation of glucose• 3 molecules of Glucose-6-P enter simultaneously in this pathway to produce 3

molecules of CO2, 6 NADPH , 2 fructose-6-P and one molecule of glyceraldehyde-3-P.

• 2 molecule of Fructose-6-P are converted to 2 molecule of Glucose-6-P while Glyceraldehyde-3-P is presumed to be equivalent to half a molecule of Glucose-6-P.

• Three carbons less are presumed to be lost as CO2. • If 6 molecules enter at the same time then it would represent loss of 6

molecules of CO2 equivalent to complete oxidation of one molecule of glucose.


Significance of HMP PathwayMajor outcomes:• NADPH• Pentoses• Glycolytic intermediates• CO2


Significance of NADPH

NADPH is mainly used for reductive biosynthesis. Additionally it is used for maintenance of membrane integrity of red blood cell and lens, detoxification and macrophageal functions.


Significance of Pentoses

Pentoses

Nucleic acids

ATP

Glycoproteins

Coenzymes


Utilization of Pentoses

Pentoses

Degradation of

coenzymes

DietaryDegradat

ion of Nucleic acids Non-oxidative phase-HMP

Pathway


Significance of Glycolytic intermediates• Glyceraldehyde-3-P and fructose-6-Pformed from 5‐C

sugar phosphates may enter Glycolysis for ATP synthesis or may be used as intermediates of pathway of gluconeogenesis.

• The Pentose Phosphate Pathway thus serves as an entry into Glycolysis for both 5‐carbon & 6‐carbon sugars.


Significance of CO2

• CO2 produced from this pathway can be utilized for CO2

fixation reactions, Such as:• Pyruvate to Oxaloacetate• Acetyl co A to Malonyl co A• Propionyl co A to Methyl malonyl co A• Gamma carboxylation of glutamic acid residues etc.


Clinical significance• Glucose-6-phosphate dehydrogenase (G6PD) deficiency• An X-linked disorder• Asymptomatic or Hemolytic anemia• Anemia may be associated with hemogobinemia and

hemoglobinuria• Acute HA can develop as a result of three types of triggers: (i)

fava beans, (ii) infections, and (iii) drugs like- Antimalarial, antibiotics, Antipyretics/ analgesics, sulfonamides etc.


Pathophysiology Of Hemolytic Anemia

• Reduced glutathione (GSH), a tripeptide with a free sulfhydryl group, is required to combat oxidative stress and maintain the normal reduced state in the cell.

• Oxidized glutathione (GSSG) is reduced by NADPH generated by glucose 6-phosphate dehydrogenase in the pentose phosphate pathway.

• Cells with reduced levels of glucose 6-phosphate dehydrogenase are especially sensitive to oxidative stress.


Treatment of Hemolytic Anemia in G6PD deficiency• Identification and discontinuation of the precipitating agent is critical

in cases of glucose-6-phosphatase dehydrogenase (G6PD) deficiency. • Affected individuals are treated with oxygen and bed rest, which may

afford symptomatic relief. • Prevention of drug-induced hemolysis is possible in most cases by

choosing alternative drugs.

Thank you1) Further reading2) http://www.namrata.co/hmp-pathway-lecture-1/3) http://www.namrata.co/hmp-pathway-lecture-2/4) http://www.namrata.co/regulation-and-significance-of-h

mp-pathway-lecture-3/5) http://bit.ly/2hUhjUc

http://www.namrata.co/hmp-pathway-lecture-1/



http://www.namrata.co/regulation-and-significance-of-hmp-pathway-lecture-3/

http://www.namrata.co/regulation-and-significance-of-hmp-pathway-lecture-3/

http://bit.ly/2hUhjUc

HMP Pathway- A Quick Revision

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