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The Role of Key Players in Cell Signaling Pathways, 5' AMP activated…

- - - - Triacylglycerol Lipase (TG Lipase): This enzyme catalyzes the hydrolysis of triacylglycerol (TAG) into free fatty acids and glycerol, which can be used for energy production. TG lipase is highly active in adipose tissue, where it mobilizes stored fats during fasting or exercise.
      - Hormone-Sensitive Lipase (HSL): HSL is an enzyme that is activated in response to hormonal signals like adrenaline and glucagon. It breaks down stored triglycerides in adipocytes (fat cells) to release fatty acids for energy production during periods of low carbohydrate availability.
      - Pancreatic Lipase: This enzyme is critical for the digestion of dietary fats. It breaks down triglycerides in the small intestine into monoglycerides and free fatty acids, which can be absorbed by the intestinal cells.
    - - Phospholipase A2 (PLA2): PLA2 enzymes hydrolyze the sn-2 acyl bond of phospholipids, releasing arachidonic acid, a precursor for eicosanoids (prostaglandins, thromboxanes, leukotrienes). These signaling molecules are involved in inflammation and other physiological processes.
      - Phospholipase C (PLC): PLC enzymes cleave the phosphodiester bond of phosphatidylinositol 4,5-bisphosphate (PIP2), generating inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 mediates calcium release from intracellular stores, while DAG activates protein kinase C (PKC), both of which are important for signal transduction.
      - Phospholipase D (PLD): PLD hydrolyzes phosphatidylcholine (PC) to produce phosphatidic acid (PA) and choline. PA is a lipid second messenger that plays a role in membrane trafficking, cytoskeletal organization, and cell signaling.
    - - FAS: Fatty Acid Synthase is a multi-enzyme complex that catalyzes the synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA in the cytosol. It is crucial in adipocytes for the storage of energy as fat and in the liver for the synthesis of fatty acids that are incorporated into lipoproteins.
    - - LPL: Lipoprotein lipase is an enzyme located on the endothelial surface of capillaries in adipose tissue, muscle, and the heart. It hydrolyzes triglycerides in circulating chylomicrons and very low-density lipoproteins (VLDL) into free fatty acids, which are then taken up by cells for energy or storage.
    - - Cholesteryl Ester Hydrolase (CEH): CEH enzymes catalyze the hydrolysis of cholesteryl esters to free cholesterol and fatty acids. This reaction is essential in the mobilization of cholesterol from intracellular stores, particularly in steroidogenic tissues where cholesterol is a precursor for steroid hormones.
      - Hormone-Sensitive Cholesteryl Esterase: Similar to hormone-sensitive lipase, this enzyme is activated by hormonal signals and plays a crucial role in the regulation of cholesterol homeostasis, particularly during stress or fasting.
    - - Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K): This enzyme phosphorylates phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PIP2), a crucial lipid that serves as a substrate for PLC and regulates various cellular processes, including cytoskeletal organization and membrane trafficking.
      - Diacylglycerol Kinase (DGK): DGK phosphorylates diacylglycerol (DAG) to produce phosphatidic acid (PA). This reaction is critical in terminating DAG-mediated signaling and in generating PA, which has signaling functions in its own right.
    - - Acid Lipase: Found in lysosomes, this enzyme is responsible for breaking down cholesteryl esters and triglycerides within lysosomes, releasing free cholesterol and fatty acids that can be used by the cell. Mutations in this enzyme can lead to lysosomal storage diseases like Wolman disease and cholesteryl ester storage disease.
    - - Ceramide Synthases: These enzymes catalyze the formation of ceramide from sphinganine (a long-chain base) and fatty acyl-CoA. Ceramide is a central molecule in sphingolipid metabolism and plays important roles in regulating cell growth, differentiation, and apoptosis.
    - - ACC1 and ACC2: ACC is a key enzyme in the biosynthesis of fatty acids. It catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, the first committed step in fatty acid synthesis. ACC1 is primarily involved in lipogenesis (fatty acid synthesis), while ACC2 regulates fatty acid oxidation by controlling the levels of malonyl-CoA, which inhibits carnitine palmitoyltransferase 1 (CPT1), the enzyme responsible for transporting fatty acids into mitochondria for oxidation.
    - - Acyl-CoA Synthetase (ACS): This family of enzymes activates fatty acids by attaching them to Coenzyme A (CoA), forming acyl-CoA. This activation is necessary for the fatty acids to participate in various metabolic pathways, including β-oxidation, where they are broken down to generate ATP.
      - Long-Chain Acyl-CoA Synthetase (ACSL): ACSL enzymes specifically activate long-chain fatty acids. These activated fatty acids can then be used for the synthesis of complex lipids like triglycerides or for energy production through β-oxidation.
- - - - cGMP dependent PK (PKG)
        
        cGMP activates PKG
        
        GTP--> cGMP
        by activated guanylyl cyclase
        
        Second messenger: cGMP
        
        -Membrane-bound guanylyl cyclases: These are activated by natriuretic peptides.
        -Soluble guanylyl cyclases: These are activated by nitric oxide (NO).
        
        Second messenger: NO gases
        
        contains a catalytic domain and a regulatory domain, and for its activation requires cGMP, which is synthesized by guanylyl cyclases
        
        cGMP binds to PKG causing a conformational change, which removes a pseudosubstrate domain and frees the catalytic site.
        
        The catalytic domain of PKG becomes active and phosphorylates various serine and threonine residues on target proteins.
        
        leading to a variety of cellular responses
        
        Termination of cGMP
        cGMP--> GMP
        by phosphodiesterases
        
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      - multifunctional calcium/calmodulin-dependent protein kinases (CAMKs)
        
        Calcium ions, Ca2+ bind to calmodulin, a small, ubiquitous protein that can bind up to 4 Ca²⁺ ions in cytoplasm.
        
        The binding of Ca²⁺ causing a conformational change in calmodulin, enabling it to interact with target proteins
        
        The activated Ca2+-calmodulin binding then will binds to CAMKs and activated the kinase.
        
        This activation of kinase causing a conformational change that exposes the kinase’s active site or releases an inhibitory domain.
        
        CAMKs use ATP to phosphorylate serine and threonine residues on target proteins.
        
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        Most characterized: calcium/calmodulin-dependent protein kinase II (CAM kinase II)
        
        CaMKII is a prominent member of this kinase family and is a multimeric enzyme consisting of multiple subunits (usually 12) that form a holoenzyme complex.
        These subunits can be identical or different isoforms, with each subunit having a molecular weight of approximately 50-60 kDa.
        
        In the presence of Ca²⁺-calmodulin binding, CaMKII activation involves autophosphorylation.
        
        Second messenger: Ca2+
      - Protein kinase C (PKC)
        
        has a regulatory domain that binds to autoinhibitory pseudosubstrate and inhibits its catalytic domain. This binding prevents the kinase from phosphorylating target proteins. (inactive state）
        
        PKC activated by Ca2+, DAG, IP3 and phosphatidylserine
        
        The binding induces a conformational change in PKC, leading to the dissociation of the regulatory domain/pseudosubstrate from the catalytic domain.
        
        This conformational change exposes the catalytic site, allowing PKC to become active and phosphorylate serine and threonine residues on target proteins.
        
        leading to a variety of cellular responses
        
        Activation of some PKC forms can also be through PI-3kinase pathway
      - cAMP dependent PKA
        (Protein Kinase A)
        
        cAMP activates PKA
        
        cAMP is derived from ATP
        ATP --> cAMP
        by enzyme adenylyl cyclase
        
        Second messenger: cAMP
        
        PKA phosphorylates transcription factors, including CREB and NFκB
    - - Cytosolic tyrosine kinases
        
        contain tyrosine phosphorylation capacity which membrane bound, soluble and reside in the cytoplasm of the cell or associated with the membrane proteins
        
        Janus Kinases (JAKs)
        
        -contain tandem, but non-identical, catalytic domains
        -involved in interactions with the other proteins they
        -lack both SH2 and SH3
        
        The activated JAKs phosphorylate each other and the receptor, creating docking sites for other proteins.
        
        Signal transducers and activators of transcription (STAT) proteins, which have SH2 domains, bind to these phosphorylated sites and are themselves phosphorylated by JAKs.
        
        Phosphorylated STAT proteins dimerize by binding ofphosphotyrosine residues of one STAT with another STAT's SH2 domain.
        
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        In humans there are at least seven different STAT proteins and seven JAK homology domains
      - Receptor tyrosine kinases (RTKs)
        
        all possess an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains the kinase activity
        
        Ligand binds to extracellular binding site of the receptor causing a conformational change which activates the kinase activity on the cytoplasmic side of the receptor.
        
        Phosphorylation of this kinase activity then leads to intracellular signaling
        
        Involve in：
        -Vascular Endothelial Growth Factor (VEGF)
        -Neurotrophins
        -Insulin-like Growth Factor-1 (IGF-1)
        
        Turn on :Phophotidylinositol 3-kinase (inositol pathway), GTPase-activating protein (G-Protein signaling) and mitogen activated protein kinase cascades (MAP kinases)
- - - - 2 cAMP binds to regulatory subunit
        
        Thus, dissociate catalytic subunit
        ( gets phosphorylated )
        
        PKA activate CREB
  - - - Effects of cGMP mediated through PKG
        
        Dependent protein kinase phosphorylates the
        target protein in the cell
        
        cGMP converted back to GTP by
        phosphodiesterase enzyme
  - - - GPCR activated
        
        Leads to the activation of
        phospholipase C
        
        PIP2
        
        IP3
        
        enters cytosol
        wall
        
        binds to IP3/Ca2+ channel
        attached to ER
        
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        DAG
        
        remain associated with
        plasma membrane
        
        recruit PKC
        
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  - - - Calmodulin activate calcium - calmodulin
        dependant protein kinase
        
        Calmodulin mediate the
        biological effect of Ca2+
- - - - Signal Reception: Cell signaling pathways often begin with the reception of an external signal, such as a hormone or growth factor, by a cell surface receptor.
        
        Signal Transduction: The binding of the signal to its receptor triggers a cascade of intracellular events. This can involve various proteins, second messengers, and other molecules that relay and amplify the signal.
      - Activation of Transcription Factors: As the signal transduction pathway progresses, it frequently leads to the activation or inhibition of transcription factors. This activation can occur through various mechanisms, including phosphorylation (addition of phosphate groups), binding of signaling molecules, or changes in cellular localization.
      - Gene Regulation: Once activated, transcription factors move into the nucleus (if they are not already there) and bind to specific DNA sequences in the promoter or enhancer regions of target genes. This binding can either promote or inhibit the transcription of these genes into mRNA.
      - Cellular Response: The changes in gene expression lead to alterations in cellular behavior. For example, genes involved in cell growth, differentiation, or apoptosis (programmed cell death) may be turned on or off in response to the signaling pathway.
        
        Feedback and Regulation: Transcription factors can also play roles in feedback loops, where they regulate the expression of other components in the signaling pathway to ensure the proper level of response and prevent overreaction.
- - - - Inhibit anabolic pathways that consume ATP
- - - - Important in controlling cell growth, proliferation, differentiation, transformation, and synaptic plasticity.
- - - - When haem levels are restored, haem binds to HRI again, leading to the re-inhibition of the kinase activity.
- - - - Termination of cAMP
        cAMP--> AMP
        by phosphodiesterases
        
        deactivation of PKA as the regulatory subunits rebind to the catalytic subunits, returning them to an inactive state
- - - - NO binds to guanylyl cyclase
        
        signal dilation of blood vessels