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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