Anabolic Pathways and Gluconeogenesis

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Questions and Answers

Anabolic pathways require energy and use electron donors in reduction reactions.

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Gluconeogenesis can occur without the use of glycerol, lactate, or amino acids as substrates.

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NADPH is a high energy electron carrier used in anabolic processes.

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The process of glycolysis can be simply reversed to produce glucose during gluconeogenesis.

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All metabolic processes require energy.

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Glycogen stores can last for up to 48 hours without replenishment.

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NADPH is mainly used in energy yielding reactions.

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NADH is primarily used for storing high energy phosphate bonds.

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The regulation of the PPP is mainly at the glucose-6-phosphate dehydrogenase reaction.

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Red blood cells, brain, and testes specifically need glucose as their preferred energy source.

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NADH and NADPH can be acted on by the same enzymes.

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Insulin decreases glucose-6-phosphate dehydrogenase gene expression.

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Products from the cyclical phase can feed into the glycolytic pathway.

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Anaerobic glycolysis converts glucose to pyruvate by lactate dehydrogenase.

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Pyruvate carboxylase requires ATP for the conversion of pyruvate to oxaloacetate.

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Fructose-1,6-bisphosphatase is inhibited by AMP.

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Glucose-6-phosphatase is present in all body tissues.

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The pentose phosphate pathway generates ATP during its reactions.

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Oxidative reactions in the pentose phosphate pathway produce NADPH.

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Glucokinase and hexokinase catalyze the same reaction as fructose-1,6-bisphosphatase.

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The cyclical phase of the pentose phosphate pathway produces predominantly NADPH.

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Gluconeogenesis primarily occurs in the cytoplasm and requires malate for transport across the mitochondrial membrane.

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The gluconeogenic step of converting pyruvate to oxaloacetate occurs in the endoplasmic reticulum.

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NADPH is involved in biosynthetic processes such as lipid synthesis.

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The pentose phosphate pathway is a source of atoms for purine biosynthesis.

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Inosine 5’-monophosphate is not a common intermediate in nucleotide biosynthesis.

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The activator for PRPP synthetase is AMP.

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Carbamoyl phosphate is synthesized using 2 ATP in pyrimidine biosynthesis.

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Glutamine and CO2 are the source of atoms in the pyrimidine ring structure.

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UDP and UTP are intermediates in purine biosynthesis.

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Ribonucleotide reductase converts ribonucleotides into deoxyribonucleotides.

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Folic acid acts as an inhibitor in pyrimidine biosynthesis.

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NADPH helps combat oxidative stress by regenerating reduced glutathione (GSH).

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Excessive breakdown of purine bases can lead to gout due to an excess of uric acid.

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Methotrexate and 5-FU are examples of drugs that promote dTMP synthesis.

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Adenosine deaminase deficiency can lead to severe immunodeficiency.

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All amino acids are classified as essential amino acids.

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Transamination is a process by which amine groups are moved between carbon backbones.

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Glutamine is synthesized from asparagine during amidation.

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Physiologically active amines include serotonin and dopamine.

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Non-essential amino acids can only be synthesized from other amino acids.

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Asparagine is synthesized from glutamate.

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Serine can be synthesized from 3-phosphoglycerate.

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NADPH is primarily involved in lipid synthesis and other biosynthetic reactions.

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Insulin reduces the expression of the glucose-6-phosphate dehydrogenase gene.

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The presence of a phosphate group differentiates NADPH from NADH and determines their specific enzyme interactions.

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The pentose phosphate pathway mainly functions to generate ATP for energy.

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NADH is utilized mainly in biosynthetic reactions.

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Anabolic pathways primarily use high energy compounds like ATP and NADH for their reactions.

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Glucose must be formed from alternative precursors only when glycogen stores are fully replenished.

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The irreversibility of certain glycolysis steps does not require special routes for gluconeogenesis.

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Lactate, glycerol, and glucogenic amino acids can all serve as substrates for gluconeogenesis.

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The pentose phosphate pathway generates energy in the form of NADH during its reactions.

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NADPH primarily functions as a reducing agent in anabolic reactions.

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Glycogen storage can last for more than 24 hours without being replenished.

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NADH is essential for the production of ATP through oxidative phosphorylation.

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Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate to pyruvate, which is a reversible step.

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Fructose-1,6-bisphosphatase is the gluconeogenic counterpart of phosphofructokinase.

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The only tissues capable of releasing glucose to the bloodstream are the liver and brain.

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The pentose phosphate pathway yields primarily ATP during its oxidative phase.

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Oxaloacetate can directly cross the mitochondrial membrane in its form produced by pyruvate carboxylase.

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The oxidative phase of the pentose phosphate pathway generates CO2 and 2 NADPH from one molecule of glucose-6-phosphate.

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Fructose-2,6-bisphosphate increases the rate of gluconeogenesis.

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In gluconeogenesis, glucose-6-phosphatase acts to release phosphate and is found in multiple tissues of the body.

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Glycerol, lactate, and amino acids can all serve as substrates for gluconeogenesis.

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NADH and NADPH play entirely the same roles in metabolic processes.

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NADPH is utilized exclusively in catabolic reactions.

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The pentose phosphate pathway contributes to the synthesis of deoxyribonucleotides through its intermediates.

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ATP acts as an inhibitor for the enzyme PRPP synthetase.

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Cofactors like tetrahydrofolate are crucial in the synthesis of pyrimidine nucleotides.

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Purine biosynthesis incorporates phosphorus from inorganic phosphate (Pi) as a major component.

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UMP (uridine monophosphate) is a common intermediate in purine nucleotide degradation.

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Inosine 5’-monophosphate serves as a central intermediate in purine biosynthesis.

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GTP can be synthesized from IMP through a series of sequential reactions involving ADP.

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Feedback inhibition in purine biosynthesis primarily involves PRPP as an inhibitor.

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NADPH is generated during the oxidative phase of the pentose phosphate pathway.

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Excessive breakdown of purine bases can lead to a condition called 'Gout' due to an excess of uric acid.

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Methotrexate and 5-FU act by promoting the synthesis of dTMP, aiding in cell division.

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Adenosine deaminase plays a critical role in the degradation pathway of AMP.

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Non-essential amino acids cannot be formed through transamination of ketoacids.

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Isolating purine biosynthesis involves common intermediates such as IMP.

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Glutamine synthetase reaction is not important for transporting ammonia in a non-toxic form.

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Both purines and pyrimidines can originate from the same amino acids.

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Serotonin and epinephrine are examples of amino acid derivatives that serve as physiologically active amines.

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Alanine is classified as a non-essential amino acid that can be synthesized from pyruvate via transamination.

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All amino acids are classified as non-essential, meaning they cannot be synthesized by the body.

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Gluconeogenesis primarily occurs in the nucleus of the cell.

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Lactate and glycerol can be used as substrates for gluconeogenesis.

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ATP is generated from NADH during the process of gluconeogenesis.

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The pentose phosphate pathway is essential for purine and pyrimidine biosynthesis.

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The conversion of pyruvate to acetyl CoA is a reversible process in gluconeogenesis.

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NADPH is primarily utilized in biosynthetic reactions rather than energy yielding reactions.

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Complex molecules in anabolic pathways are formed by linking simple precursors together.

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NADPH primarily serves as an energy source for catabolic processes.

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Glucose-6-phosphate is an activator for the glucose-6-phosphate dehydrogenase reaction.

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The primary substrate for gluconeogenesis is fructose.

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Both NADPH and NADH serve as electron carriers in the same types of biochemical reactions.

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Insulin decreases the expression of the glucose-6-phosphate dehydrogenase gene.

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The cyclical phase of the pentose phosphate pathway exclusively produces ribose 5-phosphate for DNA synthesis.

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Gluconeogenesis primarily occurs in the liver and kidneys, which are the only tissues that can release glucose to the bloodstream.

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The pentose phosphate pathway is a purely catabolic process that solely produces ATP.

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Fructose-1,6-bisphosphatase catalyzes the irreversible conversion of fructose-1,6-bisphosphate to fructose-6-phosphate.

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NADPH is produced during both the oxidative phase and the cyclical phase of the pentose phosphate pathway.

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PEP carboxykinase catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in both the mitochondrion and cytosol.

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The dephosphorylation of glucose-6-phosphate is carried out only by glucose-6-phosphatase present in skeletal muscle.

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During the oxidative phase of the pentose phosphate pathway, one molecule of glucose-6-phosphate is converted to two molecules of NADPH and one molecule of ribulose-5-phosphate.

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Lactate dehydrogenase converts pyruvate to lactate, not to oxaloacetate.

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Amino acids can enter the TCA cycle directly as TCA intermediates without any conversion.

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Excessive breakdown of pyrimidine bases can lead to a condition known as gout.

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Glucagon increases the rate of gluconeogenesis by decreasing levels of fructose-2,6-bisphosphate.

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All amino acids are classified as non-essential amino acids.

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The enzyme adenosine deaminase plays a crucial role in the degradation pathway for AMP.

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Methotrexate acts by promoting the synthesis of dTMP in cancer cells.

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Transamination reactions can generate non-essential amino acids from ketoacids.

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Glutamine is synthesized from glutamate through a reaction that requires AMP.

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Physiologically active amines are solely derived from non-essential amino acids.

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The presence of uric acid in excess can lead to inflammation in joints and kidneys.

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Asparagine can be synthesized from aspartate through a reaction catalyzed by asparagine synthetase.

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The carbon skeleton of amino acids is derived from ribose in the pentose phosphate pathway.

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PRPP is a crucial activator in the synthesis of purine nucleotides.

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The pentose phosphate pathway produces UTP as a primary product.

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Glutamine and CO2 supply the carbon atoms for the pyrimidine ring structure.

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AMP serves as an activator for ribonucleotide reductase.

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Ribonucleotide reductase operates specifically converting deoxyribonucleotides into ribonucleotides.

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Thymidylate synthase requires tetrahydrofolate as a cofactor.

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The feedback inhibition in nucleotide biosynthesis is primarily due to the accumulation of ribose-5-phosphate.

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Dihydropyrimidine dehydrogenase is responsible for the degradation of pyrimidines into uric acid.

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NADPH plays a key role in biosynthetic pathways such as nucleotide synthesis.

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The synthesis of OMP occurs after the addition of ribose-5-phosphate to the pyrimidine ring.

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Study Notes

Anabolic Pathways

Anabolic pathways require energy, use electron donors for reduction reactions, and build complex molecules from simple precursors.
Energy sources include ATP, NADH, and NADPH.

Gluconeogenesis

Occurs when glycogen stores are depleted and glucose must be made from other precursors.
Key precursors include lactate, glycerol, and glucogenic amino acids.
Bypasses irreversible steps of glycolysis.
Occurs in liver and kidney.

Steps of Gluconeogenesis

Carboxylation of pyruvate: Pyruvate is converted to oxaloacetate by pyruvate carboxylase. This occurs in the mitochondria.
Dephosphorylation of fructose-1,6-bisphosphate: Fructose-1,6-bisphosphate is converted to fructose-6-phosphate by fructose-1,6-bisphosphatase. This step is regulated by AMP and fructose-2,6-bisphosphate.
Dephosphorylation of glucose-6-phosphate: Glucose-6-phosphate is converted to glucose by glucose-6-phosphatase. This occurs in the endoplasmic reticulum.

Pentose Phosphate Pathway (PPP)

Occurs in the cytoplasm.
Generates NADPH and 5-carbon sugars for biosynthetic processes.
Has two phases: oxidative and cyclical.
Oxidative phase produces NADPH and ribulose-5-P.
Cyclical phase interconverts 3, 4, 5, 6, and 7-carbon sugars.

Regulation of the PPP

Regulated by glucose-6-phosphate dehydrogenase.
NADPH is a competitive inhibitor of the enzyme.
Insulin increases G6PD gene expression, increasing pathway activity in a well-fed state.

NADPH vs NADH

NADPH is used in biosynthetic reactions.
NADH is used in energy-yielding reactions (oxidative phosphorylation).
They are not metabolically interchangeable.

Uses of NADPH

Biosynthetic reactions (lipid synthesis).
Protective mechanisms (combat oxidative stress, regenerate reduced glutathione).

Nucleotide Biosynthesis

Purine biosynthesis: A, G; common intermediate is IMP.
Pyrimidine biosynthesis: C, T, U; common intermediate is UMP.

Clinical Aspects of Nucleotide Metabolism

Anti-cancer drugs often target dTMP synthesis to inhibit cell division.
Gout results from excess uric acid buildup due to purine breakdown.
Adenosine deaminase deficiency causes severe immunodeficiency.

Amino Acid Biosynthesis

Essential amino acids cannot be synthesized by the body.
Non-essential amino acids can be synthesized.

Transamination

Aminotransferases move amino groups between different carbon backbones.
Reversible reactions allow for generation of non-essential amino acids.

Amidation

Glutamine and asparagine synthesis.
Glutamine synthetase also transports ammonia in a non-toxic form.

Synthesis of Non-Essential Amino Acids

Many non-essential amino acids are synthesized from metabolic intermediates like pyruvate, oxaloacetate, and α-ketoglutarate.

Biosynthesis of Physiologically Active Amines

GABA, histamine, serotonin, epinephrine, norepinephrine, and dopamine are all amino acid derivatives.

Anabolic Pathways

Anabolic pathways require energy for the formation of complex molecules from simple precursors
Electron donors are used in reduction reactions
ATP, NADH, and NADPH are essential sources of energy for anabolism
ATP provides energy through high-energy phosphate bonds and reducing power
NADH and NADPH are high-energy electron carriers, providing reducing power for biosynthesis

Gluconeogenesis

Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors
Most tissues rely on glucose as their primary energy source
Gluconeogenesis is crucial when glycogen stores are depleted, which occurs after 10-18 hours
The primary precursors for gluconeogenesis include lactate, glycerol, and glucogenic amino acids
Gluconeogenesis cannot simply reverse glycolysis due to irreversible steps
Special pathways bypass irreversible steps, such as the conversion of pyruvate to acetyl CoA
Substrates for gluconeogenesis:
- Glycerol from triglyceride backbones
- Lactate from anaerobic glycolysis
- Amino acids converted to TCA intermediates and oxaloacetate

Carboxylation of Pyruvate

Pyruvate carboxylase converts pyruvate to oxaloacetate in mitochondria
PEP carboxykinase converts oxaloacetate to phosphoenolpyruvate (PEP) in mitochondria and cytosol
Oxaloacetate can't cross the mitochondrial membrane, so it is converted to malate or aspartate for transport

Dephosphorylation of Fructose-1,6-bisphosphate

Fructose-1,6-bisphosphatase reverses the glycolytic step catalyzed by phosphofructokinase
This step is regulated by AMP and fructose 2,6-bisphosphate, which is decreased by glucagon
Glucagon stimulates gluconeogenesis by decreasing fructose 2,6-bisphosphate levels

Dephosphorylation of Glucose-6-phosphate

Glucose-6-phosphatase releases phosphate from glucose-6-phosphate
The reaction occurs in the endoplasmic reticulum and requires a glucose-6-phosphate translocase
Glucose-6-phosphatase is present only in the liver and kidneys, which are the only gluconeogenic tissues.

Gluconeogenesis and Glycolysis Compared

Gluconeogenesis bypasses irreversible steps in glycolysis
Gluconeogenesis requires energy (2 ATP and 2 GTP)

Pentose Phosphate Pathway (PPP)

PPP is an anabolic pathway producing NADPH and 5-carbon sugars for biosynthesis
It is more anabolic than catabolic and occurs in the cytoplasm.
PPP produces a significant portion of the body's NADPH
The pathway consists of two phases:
- Oxidative phase: produces NADPH
- Cyclical phase: produces 5-carbon sugars

PPP and Glycolysis Interconnection

Glucose-6-phosphate (G6P) from glycolysis enters the PPP
PPP produces NADPH and ribose-5-phosphate for biosynthesis
Some intermediates re-enter glycolysis

PPP Regulation

The rate and direction of the PPP are influenced by the supply of G6P and the demand for intermediates
The pathway is mainly regulated at the glucose-6-phosphate dehydrogenase step.
NADPH acts as a competitive inhibitor of glucose-6-phosphate dehydrogenase.
Insulin increases G6PD expression to boost pathway activity during a well-fed state.

NADPH vs. NADH

NADPH – mainly for biosynthesis
NADH – mainly for energy production in oxidative phosphorylation.
NADPH and NADH generally have distinct enzymatic roles and aren't metabolically interchangeable.

NADPH Uses

Biosynthesis:
- Cholesterol
- Steroid hormones
- Sphingomyelin
- Fatty acids
- Certain phospholipids
Protection: combats oxidative stress by regenerating reduced glutathione (GSH)

Nucleotide Biosynthesis

Key elements for purine biosynthesis include:
- Pentose phosphate pathway provides ribose-5-phosphate.
- Amino acids provide nitrogenous bases.
Key elements for pyrimidine biosynthesis include:
- Glutamine and carbon dioxide are essential for the synthesis of carbamoyl phosphate
- PRPP donates ribose-5-phosphate
Common intermediates:
- Inosine 5’-monophosphate (IMP) for purine synthesis
- Orotidine 5’-monophosphate (OMP) for pyrimidine synthesis

Nucleotide Degradation

Pyrimidine bases are broken down to simple carbon skeletons
Purine bases are either salvaged for reuse or degraded:
- Purine bases are converted to xanthine and then to uric acid, which is excreted.

Clinical Aspects of Nucleotide Metabolism

Many anti-cancer drugs (chemotherapy) act by inhibiting dTMP synthesis, preventing DNA replication
Excessive breakdown of purine bases can lead to gout (uric acid crystals cause inflammation in joints and kidneys)
Adenosine deaminase deficiency: enzyme deficiency leading to severe immunodeficiency

Amino Acid Biosynthesis

Essential amino acids – cannot be synthesized by the body, must be obtained from the diet
Non-essential amino acids – can be synthesized from metabolic intermediates
Amino acids are important for building proteins and other biomolecules

Amino Acid Structure

Amino
Carboxyl
Side chain (R group)

Transamination

Aminotransferases move amide groups between different carbon backbones.
Transamination reactions are reversible.
Non-essential amino acids can be generated through the transamination of ketoacids

Amidation

Glutamine synthetase converts glutamate to glutamine.
Asparagine synthetase converts aspartate to asparagine.
Glutamine synthetase also plays a critical role in transporting ammonia in a non-toxic form

Synthesis of Non-Essential Amino Acids

Alanine, aspartate, glutamate are synthesized through transaminase reactions
Glutamine and asparagine are synthesized by dedicated enzymes (glutamine synthase, asparagine synthase)
Proline is synthesized from glutamate via cyclic reactions
Serine is synthesized from 3-phosphoglycerate
Glycine is synthesized from serine

Biosynthesis of Physiologically Active Amines

Physiologically active amines are derived from amino acids
GABA, histamine, serotonin, dopamine, epinephrine, and norepinephrine are examples of physiologically active amines.

Anabolic Pathways

Anabolic pathways require energy and use electron donors for reduction reactions.
Anabolic pathways build complex molecules from simple precursors.
All anabolic processes require energy.

Energy Sources for Anabolism

ATP provides high energy phosphate bonds.
NADH and NADPH provide high energy electrons, referred to as reducing power.
NADH contributes to oxidative phosphorylation, which generates ATP.

Gluconeogenesis

Some tissues depend on glucose as their primary energy source, including red blood cells, brain, testes, and the lens of the eye.
Glycogen stores provide glucose for 10-18 hours.
When glycogen stores are depleted, glucose is produced from other precursors: mainly lactate, glycerol, and glucogenic amino acids.
Some glycolysis steps are irreversible, which requires specialized pathways for gluconeogenesis to bypass these steps.

Gluconeogenesis: Substrates

Glycerol: Glycerol is obtained from the triglyceride backbone, converted to glycerol phosphate, and eventually becomes glyceraldehyde-3-phosphate (a glycolytic intermediate).
Lactate: Lactate is produced from anaerobic glycolysis and converted to pyruvate by lactate dehydrogenase.
Amino Acids: Amino acids are converted to TCA intermediates and oxaloacetate, entering the TCA cycle. Some amino acids are converted to glycolytic intermediates.

Gluconeogenesis: Steps

Carboxylation of Pyruvate:
- Glycolytic Step: Pyruvate kinase irreversibly converts phosphoenolpyruvate to pyruvate.
- Gluconeogenic Steps:
  - Pyruvate carboxylase converts pyruvate to oxaloacetate, requiring ATP and occurring in the mitochondria.
  - PEP carboxykinase converts oxaloacetate to PEP, using GTP and occurring in both the mitochondria and cytosol.
  - Mitochondrial oxaloacetate cannot cross the mitochondrial membrane directly but is converted to malate or aspartate for transport, then reconverted in the cytosol.
Dephosphorylation of Fructose-1,6-bisphosphate:
- Glycolytic Step: Phosphofructokinase irreversibly converts fructose-6-phosphate to fructose-1,6-bisphosphate.
- Gluconeogenic Step: Fructose 1,6 bisphosphatase reverses the reaction.
- Control: Inhibited by AMP and fructose 2,6-bisphosphate. Glucagon decreases fructose 2,6-bisphosphate levels, increasing gluconeogenesis.
Dephosphorylation of Glucose-6-phosphate:
- Glycolytic Step: Hexokinase irreversibly converts glucose to glucose-6-phosphate.
- Gluconeogenic Steps: Glucose-6-phosphatase removes phosphate from glucose-6-phosphate. This requires glucose-6-phosphate translocase to transport glucose-6-phosphate into the endoplasmic reticulum.
- Tissue Specificity: Glucose-6-phosphatase is present only in the liver and kidneys, making these the only tissues capable of gluconeogenesis and releasing glucose into the bloodstream.

Gluconeogenesis and Glycolysis Contrast

Gluconeogenesis has different enzymes than glycolysis for the irreversible steps.
Gluconeogenesis requires energy (2 ATP and 2 GTP), while glycolysis generates energy (2 ATP).

Pentose Phosphate Pathway (PPP)

Also known as the hexose monophosphate shunt/pathway or phosphogluconate pathway.
Generates NADPH and 5-carbon sugars for biosynthetic processes.
More anabolic than catabolic.
Occurs in the cytoplasm.
Produces a major proportion of the body's NADPH.
Two Phases:
- Oxidative phase: Produces NADPH (the main function of this pathway).
- Cyclical phase: Generates 5-carbon sugars.

Pentose Phosphate Pathway & Glycolysis Relationship

Glucose-6-phosphate (G6P) is the starting point and can be funneled into the PPP or continue through glycolysis.

Pentose Phosphate Pathway: Oxidative Phase

Two irreversible reactions convert glucose-6-P to ribulose-5-P, CO2, and 2 NADPH.
Catalyzed by:
- Glucose 6-phosphate dehydrogenase (G6PD)
- 6-phosphogluconolactone hydrolase

Pentose Phosphate Pathway: Cyclical Phase

Reversible non-oxidative reactions interconvert 3, 4, 5, 6, and 7-carbon sugars.
Key Intermediates:
- Ribose 5-P for DNA and RNA synthesis
- Intermediates can feed into the glycolytic pathway.

Pentose Phosphate Pathway Regulation

The rate and direction of reversible reactions are determined by the supply of glucose-6-P and the demand for intermediates.
Main Regulation Point: Glucose-6-P dehydrogenase reaction:
- NADPH is a competitive inhibitor.
- Insulin increases G6PD gene expression, increasing pathway activity in a well-fed state.

NADPH vs NADH

NADPH: Nicotinamide adenine dinucleotide phosphate. Primarily used in biosynthetic reactions.
NADH: Nicotinamide adenine dinucleotide. Primarily used in energy-yielding reactions (oxidative phosphorylation).
They are not metabolically interchangeable due to the phosphate group in NADPH.

NADPH Uses

Biosynthesis: Lipid synthesis (including cholesterol, steroid hormones, sphingomyelin, fatty acids, and certain phospholipids).
Protective: Combats oxidative stress by regenerating reduced glutathione (GSH).

Nucleotide Biosynthesis & Degradation

Purine biosynthesis (A, G)
Pyrimidine biosynthesis (C, T, U)
Nucleotide degradation

Purine Biosynthesis

Source of atoms in the purine ring structure: Pentose phosphate pathway.
Key Steps:
- Precursor activation: PRPP synthetase converts ribose-5-phosphate to PRPP, using ATP. PRPP is a key intermediate in the pathway.
- PRPP amidotransferase converts PRPP to 5'-phosphoribosylamine.
- Common intermediate: IMP (inosine 5'-monophosphate).
- End products: AMP (adenine) and GMP (guanine).

Pyrimidine Biosynthesis

Key Steps:
- Carbamoyl phosphate synthetase II: Synthesizes carbamoyl phosphate.
- Orotidine 5'-monophosphate (OMP): A key intermediate in the pathway.
- Common Intermediate: UMP (uridine monophosphate).
- End products: CMP (cytosine), TMP (thymine), and UTP (uracil).

Nucleotide Degradation

Pyrimidines: Bases are broken down to simple carbon skeletons (β-Alanine or β-Aminoisobutyrate) and degraded further.
Purines: Bases are either reused (salvaged) or degraded:
- Pathway: Purine bases --> Xanthine --> Uric acid --> Excretion

Clinical Aspects of Nucleotide Metabolism

Chemotherapy: Many drugs act by inhibiting dTMP synthesis, preventing DNA replication and cell division (e.g., methotrexate and 5-FU).
Gout: Excessive breakdown of purine bases leads to uric acid accumulation, which can crystallize in the joints and kidneys, causing inflammation and pain.
Adenosine Deaminase Deficiency: Genetic deficiency in the enzyme adenosine deaminase disrupts AMP degradation, leading to severe immunodeficiency.

Key Points about Nucleotide Pathways

Source of Atoms: Amino acids for the purine and pyrimidine rings, ribose from the pentose phosphate pathway.
Common Intermediates: IMP for G, C, and OMP for C, T, U.
Regulation: Feedback inhibition and precursor activation.
Clinical Relevance: Gout (purines), chemotherapy (thymidylate synthase and dihydrofolate reductase).

Biosynthesis of Amino Acids

Essential Amino Acids: Must be obtained from the diet, cannot be synthesized by the body (arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine).
Non-Essential Amino Acids: Can be synthesized by the body (alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine).

Amino Acid Structure

A carbon skeleton attached to an amino group (NH3+).

Transamination

Function: Moves amide groups between different carbon backbones.
Reversible: Aminotransferases (enzymes) can catalyze the reaction in both directions.
Non-Essential Amino Acid Synthesis: Transamination can generate non-essential amino acids from ketoacids.

Amidation

Function: Adds amide groups to molecules.
Key Reactions:
- Glutamine synthetase: Glutamate + ATP + NH3 --> Glutamine + ADP + phosphate. Glutamine synthetase is also important for transporting ammonia in a non-toxic form.
- Asparagine synthetase: Aspartate + ATP + Glutamine --> Asparagine + AMP + PPi + Glutamate.

Synthesis of Non-Essential Amino Acids from Metabolic Intermediates

Starting Points: Glucose, 3-phosphoglycerate (3-PG), α-ketoglutarate.
Reactions:
- Alanine: Pyruvate --> Alanine via transaminase.
- Aspartate: Oxaloacetate --> Aspartate via transaminase.
- Glutamate: α-ketoglutarate --> Glutamate via transaminase or glutamate dehydrogenase (GDH).
- Asparagine: Aspartate --> Asparagine via asparagine synthase.
- Glutamine: Glutamate --> Glutamine via glutamine synthase.
- Proline: Glutamate --> Proline via a series of reactions involving cyclisation.
- Serine: 3-phosphoglycerate --> Serine via a series of reactions.
- Glycine: Serine --> Glycine via serine hydroxymethyl transferase.

Biosynthesis of Physiologically Active Amines

Active amines derived from amino acids: GABA, histamine, serotonin, epinephrine, norepinephrine, and dopamine.
Importance: Neurotransmitters, hormones, and other regulatory molecules.

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Explore the critical processes of anabolic pathways and gluconeogenesis, including their energy requirements and key steps. This quiz covers the conversion processes in the liver and kidney, focusing on the transformation of pyruvate and other precursors into glucose. Test your understanding of metabolic pathways and their regulation.