Eicosanoids: Major Classes and Effects

Major Classes of Eicosanoids

• Prostaglandins
• Thromboxanes
• Prostacyclins
• Leukotrienes
• HETEs

Synthesis of Eicosanoids

• Diacylglycerol or phospholipid is the starting material
• Arachidonic acid is released from the phospholipid
• Prostaglandin H2 (PGH2) is a key intermediate
• Different enzymes are responsible for converting PGH2 to other eicosanoids (e.g., prostaglandin D2, E2, F2α, etc.)
• Lipoxygenase enzymes are involved in leukotriene synthesis
• Thromboxanes are produced from PGH2.
• Prostacyclins are produced from PGH2.

Effects of Eicosanoids

• Induce inflammation
• Mediate pain signals
• Induce fever
• Cause smooth muscle contraction (e.g., uterus)
• Promote smooth muscle relaxation
• Protect the stomach lining
• Stimulate platelet aggregation
• Inhibit platelet aggregation
• Cause sodium and water retention

Clinical Relevance

• Elevated eicosanoids contribute to inflammation and pain
• NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs) , and lifestyle modifications such as increasing omega-3 fatty acid intake are treatment considerations

Synthesis of Hormone Derivatives of Tryptophan

• L-Tryptophan is the precursor
• Tryptophan-5-hydroxylase converts L-tryptophan to 5-hydroxytryptophan
• 5-Hydroxytryptophan decarboxylase converts 5-hydroxytryptophan to serotonin
• Serotonin N-acetyltransferase (NAT) converts serotonin to N-acetylserotonin
• Hydroxindole-0-methyltransferase converts N-acetylserotonin to melatonin

Synthesis of Hormone Derivatives of Tyrosine

• Tyrosine is the starting material
• Tyrosine hydroxylase (TH) converts tyrosine to DOPA
• DOPA decarboxylase (DDC) converts DOPA to dopamine
• Dopamine β-hydroxylase (DBH) converts dopamine to norepinephrine
• Phenylethanolamine-N-methyltransferase (PNMT) converts norepinephrine to epinephrine

Synthesis of Thyroid Hormones

• Tyrosine is the precursor for thyroid hormones
• Iodination of tyrosine residues within the protein thyroglobulin results in the formation of T4 and T3.
• Thyroid hormones are produced in the thyroid gland.

Transport of Hormones

• Peptide/protein hormones dissolve easily in plasma, but are still carried bound to carrier proteins
• Steroid/amine hormones are relatively insoluble in plasma, and mostly transported bound to proteins

Binding Proteins

• Specialized binding proteins have high affinity (strong binding), but low capacity for binding
• Non-specialized binding proteins have low affinity, but high capacity for binding

Consequences of Binding

• Prevents hormones from overacting by keeping them bound to carrier proteins
• Prolongs the effect of hormones by preventing rapid inactivation and excretion
• Prevents large fluctuations in active hormone levels
• Increased reservoir of hormone

Hormone Concentration in Blood

• Peptide hormones generally have low concentrations in the blood.
• Steroid hormones tend to have much higher levels in the blood, often with some exceptions

Patterns of Hormone Secretion

• Chronic hormone secretion maintains relatively constant levels over time.
• Acute hormone secretion responds rapidly to stimuli (often minutes or hours)
• Episodic/cyclic hormone secretion shows fluctuations and patterns.

Hormone Specificity

• Hormones only affect target tissues with specific receptors.
• Receptor numbers are not constant; they are continually degraded and replaced.
• Downregulation can occur due to prolonged hormone exposure, where the synthesis rate of receptors decreases and the rate at which they are degraded increases.
• Upregulation occurs if the synthesis of receptors increases due to hormone exposure.

Receptor Location

• Protein/peptide hormones cannot pass through the plasma membrane.
• Receptors are located on the plasma membrane.
• The structure of these receptors features extracellular, transmembrane, and cytoplasmic/intracellular domains.

cAMP Second Messenger System

• Hormones initiate signaling cascades via 2nd messengers such as cAMP.
• cAMP is generated from ATP by adenylate cyclase, and activates protein kinase.
• Protein kinase regulates several cellular responses.

Turning Off the Signal

• Ga hydrolyzes GTP to GDP, causing disassociation from adenylate cyclase, and inhibiting its activity.
• Phosphodiesterases catalyse hydrolysis of cAMP to AMP, thus terminating the signaling cascade.

Various Cellular Responses from cAMP

• Many cellular responses are triggered by cAMP, such as secretion, enzyme activation or inhibition, lipid breakdown, glycogen synthesis, glycogen breakdown, protein synthesis, differentiation, DNA synthesis, and Ca2+ transport

Amplification

• Hormone signaling is amplified at various stages within a cell.

Other Protein Hormone Receptors

• Transmembrane receptors with intrinsic tyrosine kinase activity are receptors for insulin and many growth factors.
• These receptors possess an intracellular domain, which contains an intrinsic tyrosine kinase activity.

Steroid Hormone Action

• Steroid hormones can pass through cell membranes directly and bind to receptors in the cytoplasm or nucleus.
• The hormone-receptor complex alters gene expression, leading to the synthesis of new proteins.
• This mechanism often produces a slow but more sustained cellular response.

Thyroid Hormone Nuclear Receptor

• Thyroid hormone (T3 and T4) binds to nuclear receptors, initiating a cascade that results in the synthesis of specific proteins.
• The mechanism directly affects gene expression.

Hormones Acting Via cAMP

• Specific hormones activate cAMP signaling pathways.

Hormones Acting Via cGMP

• Certain hormones utilize cGMP as a second messenger.

Hormones Acting Via Tyrosine Kinase/Phosphatase Cascade

• Certain hormones trigger downstream signaling through a tyrosine kinase/phosphatase cascade.

Hormone Second Messenger System

• Phospholipase C (PLC) pathway generates IP3 and DAG, which activates protein kinase C (PKC).
• These components regulate calcium fluxes, leading to varied cellular responses.

Explore the major classes of eicosanoids, including prostaglandins, thromboxanes, and leukotrienes. This quiz covers their synthesis, physiological effects, and clinical relevance, particularly in relation to inflammation and pain management. Test your knowledge and understanding of this important biochemical topic.