biochemistry

• 1.987 cal/mol.K or 1.987 x 10-3 Kcal/mol.K

  Unit of measurement
• T

  Absolute temperature in K
• Complexes

  • I
  • II
  • III
• Iron-sulfur (Fe-S) center of Complex I, II and III in the se proteins Iron is bound to Cysteine
• Cell signaling (Signal Transduction)

  Mechanisms by which cells communicate and affect each other
• Steps and components of signal transduction

  1. Signaling cell produce and send signaling molecule

  2. The signal travels through the extracellular environment

  3. Receive the signal by receptors (either cell-surface receptors or intracellular receptors)

  4. The receptor activate a cascade of intracellular signal transduction proteins until an effector protein is activated

  5. The effector protein mediate the response to the signal
• Response to the signal

  • Alter enzyme activities and altered metabolism
  • Change in gene expression (number of proteins and enzymes)
  • Open ion channels
  • Movement of cells through changes in cytoskeleton
  • Cell proliferation

  
• Signal transduction

  The overall process of converting extracellular signals into intracellular responses

  
• Signalling molecules

  • Hormone
  • Growth factors
  • Neurotransmitter
  • Pheromones
  • Oxygen
  • Nutrients
  • Light
  • Touch
• Types of cell Signaling

  • Endocrine Signaling
  • Paracrine Signaling
  • Autocrine Signaling
• Endocrine Signaling

  The signaling cell is gland, signaling molecule is hormone, the signal (hormone) transported in blood to the target cells
• Paracrine Signaling

  The signaling cell secrete the signal Locally (local mediators) to the extracellular fluid, this will affect only the nearby cells

  
• Autocrine Signaling

  The signaling cell secrete signal that bind to receptors on the same cell, signaling cell = Target cell
• Reasons cells communicate with each other

  • Regulate and coordinate the metabolism of the body
  • Respond of the body to changes in conditions (fed, fasted, exercise, stress)
• Metabolism

  The chemical reactions that take place in a cell that produce energy and basic materials (building blocks) needed for important life processes
• After meal (fed-state) when glucose is available

  Pancreas secrete Insulin which stimulate liver to store the excess glucose in the form of glycogen and stimulate glucose entry to cells
• Types of Hormones

  • Anabolic Hormones (stimulate Anabolism)
  • Catabolic or stress Hormones (stimulate Catabolism)
• Anabolic Hormones

  Stimulate Anabolism (building/synthesis) such as Insulin which is secreted by pancreatic β-cells after meal (fed-state) and stimulate synthesis of proteins, fat, glycogen
• Catabolic or stress Hormones

  Stimulate Catabolism (breakdown of complex molecules to simple molecules) such as Glucagon which is secreted by pancreatic α-cells during Fasting and stimulate hydrolysis of proteins, fat, glycogen, and Cortisol which is synthesized from cholesterol and secreted from adrenal cortex in response to stress, and Epinephrine which is secreted from adrenal medulla in response to stress
• Types of Cell Receptors

  • Intracellular (IC) Receptors
  • Cell surface Receptors
• Intracellular (IC) Receptors

  Found in the Cytoplasm/Nucleus, separated from the Ligand by the plasma membrane, the signal must cross the cell membrane in order to bind to the Receptor, so the ligand must be small or Hydrophobic/Lipophilic, example: Steroid hormone receptors (testosterone receptor)
• Cell surface Receptors

  The Ligand is Hydrophilic or Large, Binding of the signal to the receptor induce cascade intracellular reactions leading to desired response, example: Insulin Receptors
• Types of Cell-surface Receptors

  • Ion-channel receptors
  • G-protein coupled receptors (GPCR)
  • Tyrosine kinase-linked receptor
  • Receptors with intrinsic enzyme activity (insulin Receptor)
• Ion Channel receptor

  The receptor itself is an Ion channel with a gate, Binding of the signal to the Receptor leads to channel opening
• 1. protein Coupled Receptor (GPCR)

  When the signal bind to GPCR, a G-protein is activated, G-protein active when bind to GTP and inactive when bind to GDP, Binding of the ligan to GPCR stimulate exchange of GDP by GTP this will activate the G-protein, The activated G-protein bind to a target enzyme in the cell membrane and affect its activity
• Tyrosine kinase-linked receptors

  When the ligan bind to the receptor the receptor dimerize (2 subunits bind to each other), The receptor dimer activate intracellular enzyme Tyrosine kinase which add phosphate to tyrosine in specific intracellular enzymes and proteins
• Receptors with intrinsic enzyme activity

  The intracellular domain of the receptor has enzymatic activity (Tyrosine-kinase), When the ligan bind to the receptor the receptor dimerize and the intracellular domain is activated and add phosphate to Tyrosine in in specific intracellular enzymes and proteins (also called Receptor Tyrosine kinase RTK)
• Insulin

  An anabolic hormone, released from the pancreas (beta cells) in response to high blood glucose (Fed state), its short term (rapid) effect: increase glucose transport into cells, stimulate lipogenesis, inhibit lipolysis, increase glycogen formation, its long-term (slow) effect: changes in transcription (increased mRNA) of those genes related to fat and carbohydrate metabolism, promotes increases in cellular growth and proliferation
• How Glycogen is synthesized from Glucose

  1. Glucose enter liver cell and phosphorylated at C6 forming Glucose-6-phosphate

  2. The phosphate is transferred from C6 to C1 by enzyme called phosphoglucomutate forming Glucose-1-phosphate

  3. Glycose-1-phosphate react with UTP (Uridine-triphosphosphate) by enzyme called UDP-glucose pyrophosphorylase forming UDP-glucose (activated glucose) and pyrophosphate Ppi

  4. An enzyme called Glycogen synthase take glucose from UDP-glucose and link them together forming Glycogen this step is the rate limiting (most important step) in glycogen synthesis
• Rate limiting step

  In order to activate glycogen synthesis we need to activate Glycogen synthase
• How Insulin stimulate glycogen synthesis in liver cell during the fed-state

  1. Insulin binds to its receptor (RTK) at the surface of the liver cell

  2. The receptor dimerize and the intracellular domain of the receptor which is a Tyrosine kinase is activated

  3. The receptor phosphorylate itself then phosphorylate and activate enzyme called protein kinase B

  4. Protein kinase B phosphorylate and inactivate Glycogen synthase kinase (GSK)

  5. Now Glycogen synthase is dephosphorylated and active to synthesize glycogen
• Insulin promotes dephosphorylation and activation of glycogen synthase by inactivating glycogen synthase kinase (GSK) through phosphorylation
• During fasting pancreatic α-cells secrete hormone called Glucagon which act opposite to insulin inhibiting Glycogen synthase and activating the enzyme that degrade glycogen (Glycogen phosphorylase)
• Glucagon


  A counterregulatory hormone for insulin
• How signals mediate their action by synthesis of small molecules inside the target cells (second messengers)

  1. The extracellular signal (first messenger) bind to its receptor ant the surface of the target cell

  2. An effector enzyme is activated

  3. The effector enzyme synthesize a small molecule (second messenger) inside the target cell

  4. The second messenger activate specific kinase enzyme

  5. The kinase enzyme start a cascade of reactions that leads to the desired response
• Examples of second messengers in cell signalling

  • cAMP
  • Calcium (Ca++)
• cAMP as second messenger

  cAMP is synthesized by enzyme called Adenylate cyclase (Adenylyl cyclase) which convert ATP to cAMP and pyrophosphate, the activity of Adenylate cyclase can be controlled by signals bind to GPCR, the intracellular domain of GPCR is linked to Trimeric G-protein, the α-subunit of the trimeric G-protein can be αs (stimulate adenylate cyclase) or αi (inhibit adenylate cyclase)
• Calcium as a second messenger

  Ca2+ versatile second messenger, All eukaryotes use Ca2+ signalling, Regulates many processes, Levels controlled by release and removal (not metabolism)
• Examples of cell signaling processes

  • Vision: Opsins receptors translate electromagnetic radiation into cellular signals
  • Sense of smell: Olfactory receptors
  • Behavioural and mood regulation: GPCRs in brain bind to neurotransmitters such as dopamine, Serotonin, glutamate
  • Regulation of immune system: histamine, LT (leukotrienes) and PG (Prostaglandins) receptors bind to inflammatory mediators
  • Autonomic nervous system: GPCRs regulate automatic functions like blood pressure, heart rate, and digestive processes
  • Orphan receptors: GPCRs whose ligands are not known