BCH 208 LECTURE NOTES

Phosphogluconate Pathway
The phosphogluconate pathway, also known as the pentose phosphate pathway or the hexose
monophosphate shunt, is an essential metabolic pathway that operates alongside glycolysis in
most organisms. It plays a crucial role in cellular energy generation, antioxidant defense, and the
production of important metabolic intermediates. The phosphogluconate pathway is a series of
enzymatic reactions that occur in the cytoplasm of cells. It converts glucose-6-phosphate
(derived from glycolysis) into various products, including ribose-5-phosphate (essential for
nucleotide synthesis) and reducing equivalents in the form of NADPH (nicotinamide adenine
dinucleotide phosphate).

The Oxidative Phase of the Phosphogluconate Pathway:

The oxidative phase of the pathway involves a series of reactions that generate NADPH and
pentose sugars. The key steps in this phase are as follows:

Glucose-6-Phosphate Dehydrogenase (G6PD) Reaction:

Glucose-6-phosphate is oxidized by glucose-6-phosphate dehydrogenase, leading to the

formation of 6-phosphoglucono-δ-lactone and the reduction of NADP+ to NADPH.

6-Phosphogluconolactonase Reaction:

6-Phosphoglucono-δ-lactone is hydrolyzed by 6-phosphogluconolactonase, resulting in the

formation of 6-phosphogluconate.

6-Phosphogluconate Dehydrogenase (6PGD) Reaction:

6-Phosphogluconate is oxidatively decarboxylated by 6-phosphogluconate dehydrogenase,

leading to the formation of ribulose-5-phosphate and the reduction of NADP+ to NADPH.

The Non-Oxidative Phase of the Phosphogluconate Pathway:

The non-oxidative phase involves a series of reversible reactions that interconvert different sugar
phosphates, allowing for the production of various metabolic intermediates. The key steps in this
phase include:

Transketolase Reactions:

Transketolase transfers a two-carbon fragment from a ketose sugar to an aldose sugar, resulting
in the formation of different sugar phosphates. This step allows for the generation of ribose-5-
phosphate, which is crucial for nucleotide synthesis, as well as the production of other sugar
phosphates for biosynthetic pathways.

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Transaldolase Reactions:

Transaldolase transfers a three-carbon fragment between different sugar phosphates, contributing

to the interconversion of sugar intermediates and the generation of glycolytic/gluconeogenic
precursors.

Role and Significance of the Phosphogluconate Pathway:

The phosphogluconate pathway serves multiple crucial functions in cellular metabolism:

NADPH Production:

One of the primary roles of the phosphogluconate pathway is the generation of NADPH.
NADPH is a vital reducing agent required for biosynthetic reactions, detoxification processes,
and maintenance of cellular redox balance. It is involved in fatty acid and cholesterol synthesis,
antioxidant defense mechanisms, and reductive biosynthesis of amino acids.

Ribose-5-Phosphate Production:

The pathway generates ribose-5-phosphate, a key precursor for the synthesis of nucleotides
(DNA and RNA) and coenzymes (such as ATP, NAD+, and FAD). Ribose-5-phosphate is also
utilized in the production of certain amino acids and coenzyme Q.

Redox Balance:

The phosphogluconate pathway helps maintain the cellular redox balance by providing NADPH,
which can reduce oxidized forms of molecules. NADPH acts as a cofactor for various enzymes
involved in redox reactions, playing a vital role in protecting cells against oxidative damage and
maintaining the activity of antioxidant systems.

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Integration with Glycolysis and TCA Cycle:

The phosphogluconate pathway intersects with other metabolic pathways, such as glycolysis and
the tricarboxylic acid (TCA) cycle. It can supply intermediates for energy production via
glycolysis or divert intermediates towards anabolic processes, depending on the cellular
requirements.
The phosphogluconate pathway, or pentose phosphate pathway, is a vital metabolic pathway
involved in cellular energy generation and biosynthesis. It plays a central role in producing
NADPH for redox reactions, generating ribose-5-phosphate for nucleotide synthesis, and
maintaining cellular redox balance. Understanding the intricacies of this pathway provides
insights into cellular metabolism, redox regulation, and the synthesis of essential biomolecules.

Glyconeolysis
Glyconeolysis, also known as glycogenolysis, is a metabolic process that involves the breakdown
of glycogen into glucose molecules. It is a crucial pathway for maintaining blood glucose levels
during fasting or periods of increased energy demand.

Glycogen is a highly branched polysaccharide composed of glucose units. It serves as a readily

available energy storage molecule in animals, primarily in the liver and skeletal muscles.
Glycogen metabolism involves two main processes:

Glycogenesis:

Glycogenesis is the synthesis of glycogen from glucose molecules. It occurs when blood glucose
levels are high, and excess glucose needs to be stored for later use.

Glyconeolysis:

Glyconeolysis is the breakdown of glycogen to release glucose when energy demands increase or
blood glucose levels decrease. It is crucial for maintaining glucose homeostasis.

Glyconeolysis Process:

Glyconeolysis involves a series of enzymatic reactions that occur primarily in the liver and to a
lesser extent in skeletal muscle. The key steps of the glyconeolysis pathway are as follows:

Activation of Glycogen:

Glycogen phosphorylase is the key enzyme involved in initiating glyconeolysis. It catalyzes the
cleavage of glucose molecules from the non-reducing ends of glycogen chains, releasing
glucose-1-phosphate

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Conversion of Glucose-1-Phosphate to Glucose-6-Phosphate:
Glucose-1-phosphate is converted to glucose-6-phosphate through the action of
phosphoglucomutase. This step is necessary to incorporate glucose-6-phosphate into glycolysis
or the gluconeogenesis pathway.
Glucose-6-Phosphate Conversion to Free Glucose:
Glucose-6-phosphatase, located in the endoplasmic reticulum of liver cells, catalyzes the
hydrolysis of glucose-6-phosphate to free glucose. The free glucose is then released into the
bloodstream, contributing to the maintenance of blood glucose levels.

Glyconeolysis pathhway

Regulation of Glyconeolysis:

Glyconeolysis is tightly regulated to ensure glucose release when needed. The key regulatory
mechanisms include:

Hormonal Regulation:

Hormones such as glucagon and epinephrine (adrenaline) stimulate glyconeolysis. Glucagon

activates protein kinase A (PKA), which phosphorylates and activates glycogen phosphorylase,
leading to increased glycogen breakdown. Epinephrine acts via the same mechanism but is
released during the fight-or-flight response.

Allosteric Regulation:

The activity of glycogen phosphorylase, the rate-limiting enzyme of glyconeolysis, is regulated

by allosteric interactions. High levels of glucose-6-phosphate, ATP, and glucose inhibit glycogen
phosphorylase, preventing unnecessary glycogen breakdown.

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Physiological Significance of Glyconeolysis:

Glyconeolysis plays a crucial role in maintaining blood glucose levels and providing an energy
source during periods of increased energy demand or fasting. The significance of glyconeolysis
includes:

Glucose Homeostasis:

Glyconeolysis helps regulate blood glucose levels, ensuring a constant supply of glucose to meet
the energy needs of the brain, red blood cells, and other glucose-dependent tissues.

Energy Production:
During prolonged exercise or fasting, when glucose availability decreases, glyconeolysis
provides a source of glucose for energy production in various tissues.

Support for Gluconeogenesis:

Glyconeolysis contributes to the supply of glucose-6-phosphate, an essential intermediate for
gluconeogenesis, the process by which new glucose molecules are synthesized from non-
carbohydrate sources.

Glyconeolysis is a vital metabolic pathway that allows for the breakdown of glycogen and the
release of glucose to maintain blood glucose levels and provide energy during periods of
increased demand or fasting. Understanding the regulation and physiological significance of
glyconeolysis enhances our comprehension of glucose homeostasis and energy metabolism in the
body.

Gluconeogenesis
Gluconeogenesis is a critical metabolic pathway that allows organisms to synthesize glucose
from non-carbohydrate precursors, such as amino acids, lactate, and glycerol. It primarily occurs
in the liver, but the kidneys and intestines also contribute to a lesser extent. The pathway
operates mainly in response to low blood glucose levels, during fasting, or when dietary
carbohydrates are limited.

Key Reactions in Gluconeogenesis:

Gluconeogenesis involves a series of enzymatic reactions that bypass the irreversible steps of
glycolysis, allowing for the synthesis of glucose. The key reactions include:

Conversion of Pyruvate to Phosphoenolpyruvate (PEP):

Pyruvate, derived from various sources such as amino acids or lactate, is carboxylated by the
enzyme pyruvate carboxylase, utilizing ATP and biotin as a cofactor. This reaction occurs in the
mitochondria and produces oxaloacetate. Oxaloacetate is then converted to PEP by the enzyme
PEP carboxykinase in the cytoplasm.

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Conversion of Oxaloacetate to Phosphoenolpyruvate:
Oxaloacetate, generated from pyruvate or amino acid metabolism, is decarboxylated and
phosphorylated by the enzyme phosphoenolpyruvate carboxykinase (PEPCK) to yield PEP. This
reaction bypasses the pyruvate kinase step in glycolysis.

Conversion of Fructose-1,6-Bisphosphate to Fructose-6-Phosphate:

Fructose-1,6-bisphosphate, derived from gluconeogenesis or glycogenolysis, is dephosphorylated
by the enzyme fructose-1,6-bisphosphatase to yield fructose-6-phosphate. This step bypasses the
irreversible phosphofructokinase reaction of glycolysis.

Conversion of Glucose-6-Phosphate to Glucose:

The final step of gluconeogenesis involves the dephosphorylation of glucose-6-phosphate to
yield glucose by the enzyme glucose-6-phosphatase. This enables the release of glucose into the
bloodstream for use by other tissues.

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Regulation and Significance of Gluconeogenesis:
Gluconeogenesis is tightly regulated to maintain glucose homeostasis and provide glucose when
dietary sources are limited. Key points regarding regulation and significance include:

Hormonal Regulation:
The hormones glucagon and cortisol promote the activation of enzymes involved in
gluconeogenesis and inhibit glycolytic enzymes. Insulin, on the other hand, suppresses
gluconeogenesis and promotes glucose uptake and utilization.

Glucose Homeostasis:
Gluconeogenesis plays a crucial role in maintaining blood glucose levels within a narrow range.
During periods of fasting or low carbohydrate intake, gluconeogenesis provides a means to
generate glucose for essential tissues, such as the brain and red blood cells, which rely heavily on
glucose as an energy source.

Metabolic Flexibility:
Gluconeogenesis demonstrates the metabolic flexibility of the body by utilizing non-
carbohydrate substrates to synthesize glucose. Amino acids derived from protein breakdown,
lactate produced during anaerobic metabolism, and glycerol released from triglycerides can all
contribute to glucose synthesis via gluconeogenesis.

Energy Conservation:
Gluconeogenesis allows for the conservation of energy by recycling carbon skeletons and
generating glucose internally. Instead of solely relying on exogenous glucose sources,
gluconeogenesis provides an endogenous supply of glucose, reducing the dependence on dietary
carbohydrates and preserving glycogen stores.

Gluconeogenesis is a crucial metabolic pathway that allows organisms to synthesize glucose

from non-carbohydrate precursors. It ensures glucose homeostasis, provides an alternative
energy source during fasting or low carbohydrate intake, and demonstrates the metabolic
adaptability of the body. Understanding the intricacies of gluconeogenesis enhances our
comprehension of glucose metabolism and its regulation in different physiological conditions.

Glyconeogenesis
Glyconeogenesis, also known as glycogen synthesis, is a vital metabolic pathway that allows
organisms to convert glucose into glycogen for energy storage. It is the reverse process of
glycogenolysis and plays a crucial role in maintaining glucose homeostasis and providing a
readily available source of glucose when needed. It is a highly regulated process that primarily
occurs in the liver and to a lesser extent in muscle cells. Glyconeogenesis involves a series of
enzymatic reactions that convert glucose into glycogen, which can be stored in the liver and
muscle tissues for future use.

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Key Reactions in Glyconeogenesis:
Glyconeogenesis involves several key reactions that are distinct from those in glycolysis:

Conversion of Glucose to Glucose-6-Phosphate:

Glucose is phosphorylated by the enzyme hexokinase or glucokinase to form glucose-6-
phosphate. This phosphorylation step ensures that glucose remains trapped within the cell and
allows for further processing in the glyconeogenesis pathway.

Conversion of Glucose-6-Phosphate to Glucose-1-Phosphate:

Glucose-6-phosphate is converted to glucose-1-phosphate by the enzyme phosphoglucomutase.
This conversion involves the transfer of a phosphate group from the C6 position to the C1
position.

Conversion of Glucose-1-Phosphate to UDP-Glucose:

Glucose-1-phosphate reacts with uridine triphosphate (UTP) to form UDP-glucose, catalyzed by
the enzyme UDP-glucose pyrophosphorylase. UDP-glucose serves as the activated form of
glucose for glycogen synthesis.

Glycogen Chain Elongation:

The enzyme glycogen synthase facilitates the elongation of glycogen chains. It adds UDP-
glucose molecules to the growing glycogen chain, forming α-1,4-glycosidic linkages.

Branching of Glycogen Chains:

The enzyme branching enzyme (α-1,6-glucosyl transferase) introduces α-1,6-glycosidic linkages
to create branch points within the glycogen structure.

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Regulation and Significance of Glyconeogenesis:
Glyconeogenesis is tightly regulated to maintain glucose homeostasis and efficiently store
glucose as glycogen. Key aspects of regulation and the significance of glyconeogenesis include:

Hormonal Regulation:
Insulin, released in response to high blood glucose levels, promotes glycogen synthesis by
activating glycogen synthase. Conversely, glucagon and epinephrine, released during low blood
glucose levels, stimulate glycogen breakdown (glycogenolysis) and inhibit glycogen synthesis.

Energy Storage:
Glyconeogenesis allows for efficient energy storage by converting excess glucose into glycogen.
Glycogen serves as a readily accessible source of glucose that can be mobilized when energy
demands increase, such as during physical activity or fasting.

Glucose Homeostasis:
Glyconeogenesis helps maintain glucose homeostasis by allowing the liver to remove excess
glucose from the bloodstream and store it as glycogen. This prevents blood glucose levels from
becoming too high, which can have detrimental effects on various tissues and organs.

Storage of Glycogen in Liver and Muscle:

Glyconeogenesis is particularly important in the liver and muscle tissues. The liver acts as a
central hub for glucose regulation, storing glycogen and releasing glucose into the bloodstream
when needed. Muscle tissue, on the other hand, stores glycogen to meet its own energy demands
during exercise.

Glyconeogenesis is a crucial metabolic pathway that allows organisms to convert glucose into
glycogen for energy storage. It ensures glucose homeostasis, facilitates energy storage and
retrieval, and plays a significant role in overall glucose metabolism. Understanding the
intricacies of glyconeogenesis expands our knowledge of energy regulation and provides insights
into metabolic adaptations in different physiological conditions.