BiochemistrY

Done by :
Leen Dauod
Samer Felfel
2023-2024
HMP cycle:
- It is an abbreviation for Hexose Monophosphate Pathway.
- Could also be called as pentose phosphate pathway OR phosphogluconate pathway.
- ATP (energy) is neither produced nor consumed.
means neither synthesis nor degradation, its only purpose is to make intermediates for metabolic
body needs.
- The rate G direction of the reactions at any given time are determined by the need of the cells (i.e.
The need of intermediates in the cycle).
- Its main functions are:
✓ Production of NADPH: as a major source of it.
The importance of NADPH is to be a biochemical reductant.
✓ Production of pentoses: The importance of pentoses is to be a part of synthesis of nucleotides.
✓ Production of different types of sugars like trioses, tetroses G pentoses.
- Location: It occurs in the cytosol (Intracellular location).
- It could be divided into 2 phases:
1. Oxidative reactions: which are 2 irreversible reactions.
2. Nonoxidative reactions: which are multiple reactions G could be reversible.

❖ Oxidative reactions: (irreversible/ rate limiting step/ directing)

- Are 2 irreversible reactions:
1. Oxidation: Dehydrogenation of glucose 6-phosphate to form 6-phosphogluconolactone.
2. Decarboxylation: Hydrolysis of 6-phosphogluconolactone and formation of ribulose 5- phosphate.
- The starting material is glucose-6-phosphate.
which lead us to a connection between glycolysis G HMP cycle, the need of body rules this happen.
- leads to the formation of ribulose 5- phosphate, CO2, and 2 molecules of NADPH for each molecule
of glucose 6-phosphate oxidized.
➢ The oxidation of glucose-6-phosphate:
- The involved enzyme is Glucose-6-phosphate dehydrogenase.
it catalyzes the oxidation of the aldehyde at C1 to a carboxylic acid in ester linkage called as lactone.
- The lactone is then hydrolyzed resulting in ring opening, the product is 6-phosphogluconate.
- NADP+ serves as an electron acceptor (oxidizing agent).

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• Regulation of G6PD:
1. High levels of NADP+ activate this pathway.
2. High levels of ADP ( low levels of ATP) activate this pathway.
3. High levels of NADPH inhibit this pathway.
4. Insulin contributes indirectly to the activation of this pathway.

➢ Decarboxylation of 6-phosphogluconolactone:
- The involved enzyme is phosphogluconate dehydrogenase.
- This enzyme works to convert 6-phosphogluconate into ribulose-5-phosphate.
- NADP+ serves as an electron acceptor (oxidizing agent).
- Carbon 1 of 6-phosphogluconate is released as CO2.

❖ Nonoxidative reactions: (reversible reactions)

- The end product is ribose-5-phosphate which is important to the biosynthesis of nucleotides.
- This phase includes aldolases and ketolases which are:
1. Aldolase: transfers 2 carbon fragments.
2. Ketolase: transfers 3 carbon fragments.
- This phase can occur without the need for the first irreversible reactions.
we mean that, with the low levels of NADP+ (i.e. high levels of NADPH), we do not actually need to
synthesize it (i.e. no need to pass through oxidation reactions and production of NADPH).
so, instead, the body uses the intermediates of glycolysis (glyceraldehyde-3-phosphate G fructose-6-
phosphate) and introduce them into several conversions to produce ribose5-phosphate.

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 NADPH STRUCTURE

❖ The importance of NADPH:

• Firstly, what is the difference between NADH G NADPH?
Both of them have high reducing power in the cell, so they serve as reducing agents.
They only differ in the presence of phosphate group on one of the ribose units and thus:
✓ NADPH is used for reductive biosynthesis.
✓ NADH is used as an electron carrier in electron transport chain.
• Uses of NADPH:
1. Reductive biosynthesis:
- NADPH can be used as a source of electrons in the biosynthesis of fatty acids and steroids.
2. Reduction of highly reactive oxygen intermediates:
NADPH indirectly provides electrons for the reduction of hydrogen peroxide.
▪ Hydrogen peroxide (H2O2) [formed during aerobic metabolism]G other reactive oxygen intermediates
can cause serios damage by reaction with DNA, proteins, and unsaturated lipids of membrane,
making membranes leaky.
▪ The cells try to reduce this damage by reducing the Hydrogen peroxide (H2O2) G other reactive
oxygen intermediates and thus Glutathione peroxidase enzyme should be used as an antioxidant.
▪ This enzyme uses a reduced form of glutathione to reduce H2O2 , so detoxification occurs G
2 H2O release.

GSH + ROOH GSSG + ROH + H2O 3

GSSG + NADPH + H+ 2 GSH + NADP+
 ▪ Glutathione must be regenerated by the electrons donated by NADPH (reducing
agent), the involved enzyme is Glutathione reductase.
▪ Antioxidant chemicals: a number of intracellular reducing agents, such as ascorbate (vitamin C),
vitamin E, and -carotene (orange vegetables such as carrots)are able to reduce and thus
detoxify oxygen intermediates in cells.
3. Cytochrome P-450 monooxygenase system:
First of all, what is specific about the liver anatomically and physiologically?
The liver has a unique and dual blood supply, receiving blood from two major
vessels: the hepatic artery and the portal vein transfer blood from the GI
to the liver.
This dual blood supply is essential for the liver's various functions, including
metabolic processes, detoxification, Filtration, ETC. in contrast to other
organs that receiving only one blood vessel which is an artery.
The liver microsomal cytochrome P-450 monooxygenases enzymes
use oxygen and NADPH in order to preform modification on any
molecule gets into the liver by hydroxylation for aromatic carbon
involved in the insoluble drugs to increase its solubility in urine and
be execrated within the urine output, by this way a detoxification
has been done by liver.
The detoxification is done for highly aromatic and aliphatic compounds
like steroids, alcohols, ending up having a water-soluble compound.

4. Phagocytosis by white blood cells:

- Neutrophils and monocytes (white blood cells) have oxygen-dependent
and oxygen-independent mechanisms for killing bacteria.
- Oxygen-independent systems utilize pH changes in the phagolysosomes
and lysosomal enzymes to destroy pathogens.
- The oxygen-dependent mechanism includes the myeloperoxidase (MPO)
system and another system that involves the generation of oxygen-
derived free radicals.
- After phagocytosis has occurred, NADPH oxidase converts molecular
oxygen into superoxide (in the respiratory burst). Next superoxide is
converted into hydrogen peroxide by superoxide dismutase (SOD). In
the presence of MPO (myeloperoxidase), peroxide plus chloride ions
are converted into hypochlorous acid that kills the bacteria.
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 Glucose 6 phosphate dehydrogenase deficiency:
It is a hereditary X-linked condition.
Characterized by hemolytic anemia caused by the inability of erythrocytes (RBCs) to produce
NADPH required for detoxification.
It I considered to be the most common disease producing enzyme abnormalities in human
There are other means by which cells having mitochondria to generate NADPH which is NADP+ -
dependent malate dehydrogenase.
Since the RBCs does not containing mitochondria the only source for NADPH is the HMP, and in
the absence of G6PD enzyme the most they will be the most affected cells by oxidation cause
hemolysis
Hemolysis: is the degradation of RBCs before normal life span.
If the deficiency causes these problems…what is the role of G6PD in red blood cells?
Formation of NADPH which is essential in the detoxification of free radicals and peroxides
formed within the cell.
All cells of the affected individual have an enzyme deficiency. But it is most severe in
erythrocytes (RBCs) where the HMP provides the only mean of generating NADPH whereas
other tissues have other NADPH sources such as NADP+-dependent malate dehydrogenase.
• Precipitating factors in G6PD deficiency:
Some factors precipitate the hemolytic anemia in G6PD deficiency patents:
1. Oxidant drugs: like antibiotics e.g. sulfamethoxazole, Antimalarials e.g. primaquine
2. Favism (‫)التف ّول‬: The hemolytic effect of ingesting fava beans is observed in patients with
favism (G6PD deficiency).
3. Infection: The inflammatory response to infection results in the generation of free radicals
in macrophages, which can diffuse into the red blood cells and cause oxidative damage.
Neonatal jaundice: Neonatal jaundice may occur in infants with G6PD deficiency. This
condition can result from impaired hepatic catabolism of bilirubin or increased production
of bilirubin.(which is a product of the breakdown of red blood cells, and if its metabolism is
impaired, it can accumulate in the bloodstream, leading to jaundice).

The End