INTERORGAN METABOLIC PATHWAYS

How does the various organs interact and what is the flow of metabolites among them?

Cori Cycle (Fig. 21-6)

· In Muscle:

o Fast-twitch muscle metabolizes glucose to lactate for formation of ATP.

o Slow-twitch muscle usually generate energy by Oxi Pho but also produces lactate when ATP demand exceeds oxidative flux.

· Lactate is transported from muscle to liver via bloodstream.

· Muscle does not have glu-6-phosphatase, hence no gluconeogenesis from G6P.

· In Liver:

o Lactate is re-converted to pyruvate for gluconeogenesis.

o Gluconeogenesis requires ATP and GTP.

o The consumed ATP is regenerated through Oxi Pho.

· Separation of the ATP-generation glycolysis and the ATP-consuming gluconeogenesis processes in two separate organs.

· The combination of these two processes in a single cell would be a futile cycle.

Glucose-Alanine Cycle (Fig. 21-7)

· In Muscle:

o Glucose and glycogen (via G6P) enter glycolysis to generate pyruvate and ATP.

o Transaminase allows (AA + Pyruvate ⇌ α–Keto acid + Alanine)

· Alanine is transported from muscle to liver via bloodstream

· In Liver:

o Alanine is re-converted to pyruvate for gluconeogenesis.

o Gluconeogenesis requires ATP and GTP.

o The consumed ATP is regenerated through Oxi Pho.

o The alanine amino group is recovered in NH₄⁺ or aspartate à urea synthesis.

· Separation of the ATP-generation glycolysis and the ATP-consuming gluconeogenesis processes in two separate organs.

· This cycle also allows the transfer of nitrogen from muscle to liver.

HORMONE ACTION: SIGNAL TRANSDUCTION

In Animals:

· Endocrine glands synthesize and release hormones.

· Hormones are carried by bloodstream to target cells.

· Binding of hormone to specific receptor on the surface of target cells.

· The binding of an extracellular ligand elicits, via the receptor, a discrete biochemical effect inside of cell. This is signal transduction.

· Signal transduction pathways are very complex, allowing cells to react to discrete signals (individually or in combination) with variations in the magnitude and duration of their responses.

Hormones Control Fuel Metabolism by:

· Maintaining homeostasis (e.g. constant blood glucose)

· Responding to a wide variety of stimuli (e.g. via epinephrine and norepinephrine)

· Follow cyclic and developmental programs (e.g. maturation, sexual differentiation, etc.)

The Adenylate Cyclase Signaling System

· Adrenal gland cortex (outer layer) synthesizes and secretes steroid hormones.

· Adrenal gland medulla synthesizes and releases epinephrine and norepinephrine.

· Epinephrine and norepinephrine can bind to a class of integral membrane glycoprotein receptors.

· These receptors are structurally typified by (a) an extracellular glycosylated N-terminal domain, (b) 7 tranmembrane hydrophobic helices, and (c) an intracellular C-terminal domain.

Mechanism of Adenylate Cyclase System (See Fig. 21-15)

· Binding of hormone to extracellular glycosylated receptor site.

· Conformational change of the receptor protein intracellular C-terminal domain

· The receptor intracellular domain, in its new conformation, interacts with an abg heterotrimeric G-protein (G_s, or G, or s in Fig. 21-15) for its activation.

· G_sα•GTP activates plasma membrane-bound adenylate cyclase.

· Formation of intracellular cAMP – a “second messenger”

· Binding of cAMP to inactive cAMP-dependet protein kinase R₂C₂ induces the dissociation of 2 active C from R₂:cAMP.

· Phosporylation of Ser or Thr residues of cellular proteins for specific responses.

· G_sα is an GTPase, allowing turnover of active G_sα•GTP to G_sα•GDP and subsequent formation of inactive G_sαbg•GDP.

Regulation via Inhibitory G-Protein

· An inhibitory G-protein (Gi) offers regulation following a similar set of events except that G_iα•GTP inactivates adenylate cyclase.

Receptor Tyrosine Kinases

· Many protein hormones known as growth factors stimulate the proliferation and differentiation of target cells by binding to Receptor Tyrosine Kinases (RTKs).

· Structurally they are typified by (a) an extracellular hormone binding domain, (b) a single trans-membrane domain, and (c) an intracellular tyrosine kinase domain.

Mechanism of RTKs

· Usually RTKs exist as monomers. Example: human growth hormone receptor.

· A single hormone molecule binds to two monomeric RTKs to form a complex.

· The complex formation of the two intracellular domains actives the tyrosine kinase activity.

· Results in mutual cross-phosphorylation of Tyr residues of the kinase domains.

· This autophosphorylation activates Tyrosine Kinase activity, enabling subsequent phosphorylation of tyrosine residues of intracellular proteins.

· The activated RTK can also bind certain cytoplasmic protein tightly, via interactions between a SH2 domain of the latter with the phosphorylated tyrosine residues of RTK.

· This binding leads to phosphorylation of the cytoplasmic protein or a change of its conformation to trigger a subsequent sequence of cellular events (involving a monomeric G-protein named Ras).

· Protein tyrosine phosphatases serve as an “off switch” for RTKs.

The Dimeric Insulin Receptor

· A transmembrane glycoprotein with tyrosine kinase activity.

· In the unliganded state, it exists as a dimer of two (αβ) monomers. (Fig. 21-16)

· The α is entirely in the extracellular space and the β spans through the membrane.

· When insulin binds to two α subunits, a conformational change occurs in the intracellular domain of β, enabling autophosphorylations and activations of tyrosine kinase activity.

· The activated kinase domain does not interact directly with any SH2-containing proteins.

· However, the activated kinase domain can bind and phosphorylate a number of proteins, mainly the insulin receptor substrate-1 and 2 (IRS-1 and IRS-2).

· The phosphorylated IRS-1 and IRS-2 can then bind certain SH2-containing proteins.

The Phosphoinositide Pathway (Fig. 21-22)

· Phosphatidylinositol-4,5-bisphosphate (PIP2), a minor structural component of plasma membranes, is a part of a second messenger system.

· Binding of exacellular ligand to a receptor (also containing a 7 transmembrane segments) enables the inateraction with an αβg hetertrimeric G-protein (Gq or q in diagram).

· Formation of active qα•GTP, which activates a membrane-bound phospholipase C (PLC).

· Enabling hydrolysis of PIP2 to form inositol-1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG)

· IP₃ is a water-soluble second messenger:

o Binds to and induces the opening of a Ca²⁺ transport channel in endoplasmic reticulum, allowing efflux of Ca²⁺ to significantly increase cytosolic [Ca²⁺].

o Triggers diverse cellular responses.

· DAG is a lipid-soluble second messenger:

o Remains in plasma membranes

o Activates several cellular proteins.