Lecture 18: Integration

Intermediary Metabolism – Principles ATP is the universal

“energy currency”

ATP is used in____

biosynthesis

ATP is generated by____

oxidation of fuel molecules

ATP generated from molecules such as____

Sugars and carbohydrates, Fatty acids, Amino acids

NAD+ is the major electron acceptor in____

catabolism

NADPH is the major electron donor in____

reductive biosynthesis

Biomolecules are catabolized to, and constructed from,____

a relatively small set of building blocks

Biosynthetic and degradative pathways are almost always____

distinct, especially at key steps

Acetyl-CoA and pyruvate are____

key junctions

Pyruvate → acetyl-CoA: Unidirectional in____

vertebrates

Recurring themes of metabolic regulation____

Regulation of pathways, at specific steps, irreversible, committed, control of enzymatic activity, control of enzyme levels, allosteric interactions, covalent modification, subcellular compartmentalization

Factors affecting the activity of enzymes

extracellular signals, regulatory proteins…

Division of labor____

organ specialization

Liver

sugar metabolism

G6P has several fates____

glucose for export, glycogen for storage, oxidation for energy production, Acetyl-CoA ® lipids for storage, pentose phosphate pathway for reducing power & Ribose 5-P

Liver

amino acid metabolism

Amino acids have several fates____

proteins in liver, transport in blood to other organs, precursors Nucleotides, biological amines, hormones…, deamination, deamination of Ala (from muscle)

Carbon skeletons go to____

citric acid cycle for energy, glucose, glycogen, lipids for transport and storage

Ammonia is____

recycled, or excreted (® urea)

Deamination of Ala (from muscle)____

pyruvate ® glucose for transport

Liver

lipid metabolism

FAs have several fates____

liver lipids for storage, acetyl-CoA, oxidation for energy and NADH, ketone bodies for transport, cholesterol membranes, hormones, TAGs & phospholipids for transport in lipoproteins, direct transport in blood, bound to serum albumin

Adipose tissues____

store and supply fatty acids

White adipocytes____

Fuel Storage/Fuel Mobilization

Brown adipocytes____

thermogenesis (UCP1)

phosphocreatine

“Stored ATP”

ATP is used to generate____

mechanical work

Creatine is formed from____

glycine, arginine, and methionine

Creatine is much more abundant than____

ADP

Phosphocreatine is a reservoir of____

“high-energy” phosphate

The Cori cycle is an example of____

an inter-organ pathway

After heavy exertion, increased O2 consumption allows____

replenishment of muscle glycogen, replenishment of P-creatine, gluconeogenesis in the liver

Overall, the Cori Cycle is less efficient than____

simply burning glycogen to CO2 in the muscle, but it allows for a rapid burst of energy use.

The brain____

Prefers glucose, Needs lots of ATP (~15% of total daily energy requirement), Ketone bodies can be used when glucose is unavailable

Plasma concentration of____

glucose, ketone bodies and fatty acids in starvation

ketones are

beta hydroxybutyrate, acetoacetate, acetone

Fuel metabolism in the liver during prolonged fasting

increased lipolysis, b oxidation, ketogenesis, ketone bodies; decreased [OAA], TCA cycle, [NAD(P)H]

Hormonal signaling allows coordinated regulation of____

metabolic pathways

Hormones are____

chemically diverse

Insulin is formed by____

proteolytic processing

Some hormones are released in____

a cascade

A cascade includes____

Neuronal and hormonal signals, Signal amplification, Feedback regulation

Two-way information flow between____

tissues and the hypothalamus

Peptide hormones released by the intestine, stomach and adipose tissue feed back on the hypothalamus to____

signal satiety and reduce feeding behavior.

Major Hormones Controlling Fuel Metabolism: what does glucagon and glycogen do?

Glucagon is secreted by the pancreas in response to low blood glucose; Insulin is secreted by the pancreas in response to high blood glucose

Glucagon

secreted by pancreas in response to low blood glucose, promotes glucose generation (gluconeogenesis, glycogen break down), reduce glucose utilization (decrease glycolysis and glycogen synthesis)

insulin

secreted by pancreas in response to high blood glucose, promoted glucose update (drecrease blood glucose), reduce glucose generation (decrease glycogen breakdown), promotes fuel storage (increase glycogen synthesis, increase Fatty acity and TAG synthesis)

Glucagon and insulin act in____

opposition

In some cases, glucose and insulin act on the____

same target enzyme

Epinephrine signals____

impending activity

Epinephrine is secreted by____

the adrenal medulla

Epinephrine is secreted in response to____

low blood glucose

Epinephrine regulates____

(activate) glucagon and (inhibit) insulin

Metabolic defects in diabetes____

Insulin Deficiency, Abnormally elevated blood [glucose], overproduction of ketones

Type I____

Insulin-dependent, Insulin is not produced

Type II____

Noninsulin-dependent, Target cells are resistant to insulin

Abnormally elevated blood [glucose]____

glucose uptake is blocked in muscle and adipose, gluconeogenesis is stimulated in liver, hyperglycemia and glucosuria, dehydration, osmotic diuresis

Overproduction of ketone bodies____

fatty acid oxidation is stimulated in adipose, ketogenesis is stimulated in liver, ketoacidosis

What we have (diabetes) here is____

a failure to communicate!

Signal transduction____

a process by which extracellular signals are amplified and converted to a cellular response

Two general mechanisms of hormone action

cell surface receptor, nuclear receptor

Features of signal transduction systems

specificity, sensitivity, amplification

Four general types of signal transducers

g coupled receptor, gated ion channel, receptor enzyme, nuclear receptor

Epinephrine signals through____

the b-adrenergic receptor (a G-protein coupled receptor)

epinephrine: 2nd Messenger____

cAMP

GPCR signaling through other second messengers____

Hormone-activated phospholipase C produces the second messengers inositol trisphosphate (IP3), diacylglycerol and (indirectly) Ca2+.

Formation of cyclic AMP by____

adenylyl cyclase, degradation by a phosphodiesterase

Self-inactivation of g proteins

bound to GDP, Gs, with beta, alpha, y subunit

active g proteins

GTP just alpha subunit

The epinephrine cascade____

Activation of catalysts by catalysts results in signal amplification

With only a 10- or 20-fold amplification per stage____

10,000-fold amplification overall.

Cholera toxin locks Gsα in____

the active state

_____ ______ in activates GTPase activity of signal transducers

ADP ribosylation

Hormone-activated phospholipase C produces the second messengers

inositol trisphosphate (IP3), diacylglycerol and (indirectly) Ca2+

Calmodulin mediates____

Ca2+-stimulated enzymatic actions

Upon binding Ca2+____

calmodulin undergoes a large conformational change, exposing a hydrophilic helix.

The helix interacts with target proteins by____

wrapping around an activating domain of the protein

Insulin receptor is____

a receptor tyrosine kinase

Activation by____

conformational change and autophosphorylation.

Phosphorylation repositions____

the activation loop away from substrate-binding site.

The receptor phosphorylates____

target proteins to regulate their activity.

Insulin signaling____

a kinase cascade

A kinase cascade includes____

Amplification, a single activated receptor can activate several IRS-1 molecules, Integration, activation of IRS-1 through multiple receptors, triggering of multiple signaling pathways through IRS-1 (Grb2 is not the only target of IRS-1)

Insulin action on____

glycogen synthase and glucose transport

Phosphorylated IRS1 activates____

PI3K by binding to its SH2 domain

Note that Phosphorylated IRS1 generates____

PIP3, not IP3

The SH2 domain is an example of____

a phospholipid binding module

Proteins involved in signaling at the plasma membrane have one or more____

phosphoprotein or phospholipid binding domains.

Cross talk between____

the insulin receptor and GPCRs

insulin receptor and GPCRs: Left side____

enhanced insulin signaling through a GPCR.

insulin receptor and GPCRs: Right side____

Reduced receptor response after internalization.

Steroid hormone receptors directly regulate____

gene expression

Steroid hormones____

e.g. estrogen, progesterone, vitamin D, cortisol, retinoic acid and thyroid hormones

Four general types of signal transducers

g protein coupled receptor, receptor enzyme, gated ion channel, nuclear receptor