7,integration of metabolism

16-1

Biochemistry

Chen YonggangDept. of Biochemistry

Zhejiang Univ. School of Medicine

.

16-2

Integration of Metabolism

Functions of Hormones

16-3

Overview Of Metabolism

Adult animals reach a steady state where anabolism and catabolism are approximately equal.

Intercellular communication is responsible for this steady state.

The nervous and endocrine systems are responsible for coordinating metabolism.

16-4

Overview of Metabolism-2

Neurons emit neurotransmitters that evoke specific responses from nearby cells.

Endocrine system releases hormones into the bloodstream which act either directly on a cell or via a second messenger.

Overview of metabolism is on next slide.

16-5

16-6

Division of Labor

Small Intestine

Digestion of nutrients

Into molecules small enough to be absorbed by enterocytes

To blood and lymph systems

Energy via glutamine

16-7

Division of Labor-2

Liver

Key role in carbohydrate, lipid, and AA metabolism

Regulates composition of blood

Regulates nutrients availability

Adipose Tissue

Storage of energy in form of TAGs

16-8

Division of Labor-3Brain

Directs most metabolic activityUses energy (usually glucose)

Kidney (energy via fatty acids and glucose)Filtration of blood plasmaReabsorb electrolytes, sugars and amino acids from filtrateRegulate body pHRegulate body’s water content

16-9

Feeding-Fasting Cycle

Mammals are able to consume food intermittently because of elaborate mechanisms for storing and mobilizing energy-rich molecules derived from food.

Postprandial-directly after a meal when blood nutrient levels are elevated over the fasting state.

Post absorptive- blood nutrient levels are low, e. g. overnight.

16-10

The Feeding PhaseFood propelled along gastrointestinal

tract by muscular contraction (nervous system).

Products are: sugars, fatty acids, glycerol, and amino acids.

Sugars and amino acids absorbed and transported by the portal blood to the liver.

Lipids (as chylomicrons) to muscle and adipose tissue. Chylomicron remnants to liver.

16-11

The Feeding Phase-2Glucose moves to the liver. High

concentration in blood triggers insulin release in pancreas.

Insulin triggers: glucose uptake by muscle and adipose tissue, fat synthesis in liver and adipocytes, and gluconeogenesis (liver with three C sources.)

Allosteric effectors ensure that competing pathways do not occur simultaneously.

16-12

The Fasting Phase

Nutrient flow from intestine decreases.

Blood glucose and insulin levels fall and glucagon promotes glycogenolysis and gluconeogenesis in the liver.

Low insulin levels promotes lipolysis and release of AA from muscle.

Prolonged fasting (overnight) results in FAs from adipose tissue providing glucose for muscle.

16-13

The Fasting Phase-2

Starvation

FAs (adipocytes) and ketone bodies (liver) are used for energy.

Large amounts of AAs from muscle are used for gluconeogenesis.

After several weeks, the brain uses ketone bodies for fuel.

16-14

Intercellular Communication

Endocrine hormones are chemicals secreted by special cells that exert some biochemical effect on a distant target cell.

Growth hormone (pituitary), testosterone (gonads), and insulin (pancreas) are common examples.

Some hormones target specific cells and some have effects on a variety of different cell types.

16-15

HormonesThyroid-stimulating hormone (TSH)

stimulates follicular cells in the thyroid gland to release T3 and T4.

T3 and T4 stimulate a variety of cellular

responses in numerous cell types.

Thyroid hormones stimulate glycogenolysis in liver but glucose absorption in the small intestine.

16-16

Hormone ExamplesSource Hormone FunctionHypothalmus gonadotropin-RH stimulate

LH and FSH

Pituitary growth hormone growth

oxytocin uterine contr

Gonads estrogens female repr

androgens male repr

Pancreas insulin glucose uptake

16-17

Hormone Examples-2

Hormone molecules can be:

polypeptides: ACTH, FSH, GnRH, oxytocin

steroids: estrogens, androgens, glucocorticoids

AA derivatives: epinephrine, thyroxine,norepinephrine

16-18

Cascade System-1Many hormones synthesis and

release are regulated by a “cascade mechanism” ultimately controlled by the central nervous system (CNS).

The hypothalamus directs the anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis).

16-19

Cascade System-2

hypothalamus

thyroid adrenalcortex

testesovaries

anterior pituitary

TRH GnRHCRH GHRH

TSH ACTH LH/FSH

many tissues reproductiveorgans

bone

GH

T3, T4 corticoidssexhormones

inhibit

16-20

Cascade System-3

hypothalamus

posterior pituitary

smooth musclemammary glands

oxytocin

kidney tubulesarterioles

vassopressin

16-21

Growth FactorsA variety of hormonelike polypeptides

and proteins. Called growth factors or cytokines, are thought to regulate the growth, differentiation, and proliferation of cells.

Epidermal growth factor (EGF)

A mitogen (a stimulator of cell division) for many kinds of epithelial cells.

Platelet-derived growth factor (PDGF)

Stimulates mitosis in fibroblasts.

16-22

Growth Factors-2Somatomedins (insulinlike growth

factors I and II, IGF-1 and IGF-2 in humans)

Mediate actions of growth hormone (GH).

Secreted in the liver (and other tissue cells)

16-23

Growth Factors-3Interleukin-2 (IL-2)

Also regulate the immune system.

Secreted by T cells after they have been activated by binding to a specific antigen-binding cell.

Numerous identical T cells are produced.

16-24

Growth Factors-4Interferons

Type I protect cells from viral infection by stimulating phosphorylation ins inactivation of a protein factor required for protein synthesis.

Type II (from T lymphocytes) inhibit growth of cancerous cells.

Tumor necrosis factors (TNF) are toxic to tumor cells.

16-25

Mechanisms of Hormone ActionSteroid receptors are usually within the

cell as the steroid molecules pass through the cell membrane.

Other hormones bind to specific sites on the cell membrane and release within the cell second messengers which actually cause the hormonal response.

This signal transduction also allows for a tremendous amplification of the hormone molecule’s impact on the cell.

16-26

Second MessengersCommon second

messengers are cyclic AMP (cAMP), cGMP, diacylglycerol (DAG), inositol-1,4,5-triphosphate (IP3), and Ca2+.

We will examine cAMP synthesis and action in more detail.

NH N

N N

NH2

OCH2

H

O

H

OH

HH

OPO

O

16-27

cAMPcAMP is produced when hormone binds

to a membrane receptor. This binding activates a G protein (binds guanine nucleotide) as shown on the next slide.

The stimulated G protein replaces GDP with GTP. This activates the subunit to bind to and activate adenylate cyclase which then produces cAMP.

cAMP then activates a cAMP-dependent protein kinase.

16-28

cAMP-2

GDP

hormone

inactiveG protein

adenylatecyclase

GTP

GDP

GTP

hormone

activeG protein

adenylatecyclase(actived)

16-29

cAMP-3Adenylate cyclase stays activated until

the GTP on the subunit of the G protein is hydrolyzed back to GDP.

Thus a single hormone molecule (eg. glucagon) can stimulate synthesis of many cAMP molecules which in turn can turn on phosphorylation and activate, for example, multiple phosphorylase kinase molecules to hydrolyze glycogen to G-1-P.

16-30

cAMP-4Adenylate cyclase is deactivated when

the subunit of the G protein uses its built in hydrolysis capability to return GTP to GDP.

Before this occurs, however, many protein molecules have been activated. This is the “cascade” process referred to earlier.

16-31

cGMPFrom GTP by guanylate cyclase

Two types of guanylate cyclase are involved in signal transduction, one is membrane bound and the other cytoplasmic.

Membrane bound activated by:

Atrial natriuretic factor (ANF) peptide

Bacterial enterotoxin

16-32

cGMP-2ANF is released by atrial heart cells

responding to increased blood volume.Lowering blood pressure and diuresis

seem to be mediated by cGMP.Binding of enterotoxin to intestinal cells

causes diarrhea via excessive secretion of electrolytes and water into the lumen of the small intestine.

Cytoplasmic guanylate cyclase may bind NO to a heme group to activate the enzyme.

16-33

Phosphatidyl Inositol and Ca2+

The phosphatidyl inositol cycle (slide 36) mediates the action of hormones and growth factors

Phosphatidyl inositol-4,5-bisphosphate (PIP2) is cleaved by phospholipase C to

form second messengers DAG and IP3

(inositol-1,4,5-triphosphate)

DAG activates protein kinase which activates or deactivates an enzyme.

16-34

Phosphatidyl Inositol and Ca2+ -2IP3 diffuses to the calcisome (SER)

where it binds to a receptor, a calcium channel.

Calcium flows in to the cytoplasm regulating calcium-binding proteins.

Calmodulin mediates many calcium-regulated reactions. It is a regulatory subunit for some enzymes (e. g. phosphorylase kinase important in glycogen metabolism).

16-35

Fig 16.12

16-36

Steroid Hormone MechanismSignal transduction by hydrophobic

hormones (e. g. steroids) result in changes in gene expression.

i. e. protein mix changes in the cell.Transport into the cell is via binding to a

protein.E. g. : transcortin

androgen-binding proteinsex hormone-binding

proteinalbumin

16-37

Steroid Hormone Mechanism-2In the cell, hormones bind to

intracellular receptors. The complex moves to the nucleus. (Slide 39)

In the nucleus, each complex binds to specific DNA segments, called hormone response elements (HRE), via a zinc finger domain.

The receptor enhances or diminishes transcription of a specific gene.

Each HRE may influence 50-100 genes.

16-38

16-39

The Insulin ReceptorThe insulin receptor (Slide 41) is a trans-

membrane glycoprotein with two subunits connected by disulfide bridges.

Insulin binding activates receptor tyrosine kinase activity and causes a phosphorylation cascade that modulates intracellular proteins.

Binding also induces transfer of some proteins to the cell surface.

16-40

16-41

The EndIntegration

of

Metabolism