2. the cell and its function and genetic control of protein

U N I T I

Textbook of Medical Physiology, 11th Edition

GUYTON & HALL

Copyright © 2006 by Elsevier, Inc.

Chapter 2:The Cell and its Functions

Slides by John E. Hall, Ph.D. and Louise C. Nuttle, Ph.D.


Organization of the Cell

Figure 2-1


Cell Composition

WaterIons

ProteinsLipids

Carbohydrates

...70-85% of cell mass

...10-20%

...2-95%

...1-6%


Membrane Components:

• barrier to water and water-soluble substances• organized in a bilayer of phospholipid molecules

hydrophilic“head”

hydrophobicFA “tail”

ions H2O urea

CO2

LIPIDS:

O2N2

halothaneglucose


Cell Membrane: Bilayer of Phospholipids with Proteins

Figure 2-3


• provide “specificity” to a membrane• defined by mode of association with the lipid bilayer– integral: channels, pores, carriers, enzymes, etc.– peripheral: enzymes, intracellular signal mediators

K+

Proteins:


• glycolipids (approx. 10%)• glycoproteins (majority of integral proteins)• proteoglycans

GLYCOCALYX

Carbohydrates:


• negative charge of the carbo chains repels other negative charges• involved in cell-cell attachments/interactions• play a role in immune reactions

GLYCOCALYX

(-) (-) (-) (-)(-)

(-)(-)

Carbohydrates (Cont.):


• present in membranes in varying amounts• generally decreases membrane FLUIDITY and PERMEABILITY (except in plasma membrane)• increases membrane FLEXIBILITY and STABILITY

(-) (-) (-) (-)(-)

(-)(-)

Cholesterol:


Figure 2-2

Cell Organelles


The Endoplasmic Reticulum:• Network of tubular and flat vesicular structures• Membrane is similar to (and contiguous with) the plasma membrane • Space inside the tubules is called the endoplasmic matrix

Figure 2-4


• outer membrane surface covered with ribosomes

• newly synthesized proteins are extruded into the ER matrix

• proteins are “processed” inside the matrix - crosslinked - folded- glycosylated (N-linked)- cleaved

Rough or Granular ER

Figure 2-13


• site of lipid synthesis- phospholipids- cholesterol

• growing ER membrane buds continuously forming transport vesicles, most of which migrate to the Golgi apparatus

Smooth ER

Figure 2-13


The Golgi Apparatus:

• Membrane composition similar to that of the smooth ER and plasma membrane• Composed of 4 or more stacked layers of flat vesicular structures

Figure 2-5


• Receives transport vesicles from smooth ER

• Substances formed in the ER are “processed”

- phosphorylated- glycosylated

• Substances are concentrated, sorted and packaged for secretion.


Secretory vesicles diffuse through the cytosol and fuse to the plasma membrane

Exocytosis:

Lysosomes fuse with internal endocytotic vesicles


Secretion:

• secretory vesicles containing proteins synthesized in the RER bud from the Golgi apparatus

• fuse with plasma membrane to release contents

- constitutive secretion - happens randomly- stimulated secretion - requires trigger


Lysosomes:

• contain hydrolytic enzymes (acid hydrolases)

- phosphatases- nucleases- proteases- lipid-degrading enzymes- lysozymes digest bacteria

• vesicular organelle formed from budding Golgi

• fuse with pinocytotic or phagocytotic vesicles to form digestive vesicles

Figure 2-12


Lysosomal Storage Diseases

Absence of one or more hydrolases• not synthesized• inactive• not properly sorted and packaged

Result: Lysosomes become engorged with undigested substrate

Examples:• Acid lipase A deficiency• I-cell disease (non-specific)• Tay-Sachs disease (HEX A)


Peroxisomes:

• similar physically to lysosomes

• two major differences:• formed by self-replication • they contain oxidases

Function: oxidize substances (e.g. alcohol) that may be otherwise poisonous


Secretory Granules

Figure 2-6


Mitochondria:

Primary function: extraction of energy from nutrients

Figure 2-7


The Nucleus: “Control Center” of the Cell

The double nuclear membrane and matrix are contiguous with the endoplasmic reticulum

Figure 2-9


• 100 nm in diameter

• functional diameter is ~9 nm

• (selectively) permeable to molecules of up to 44,000 MW

The nuclear membrane is permeated by thousands of nuclear pores

Figure 2-9


Chromatin (condensed DNA) is found in the nucleoplasmNucleolus

• one or more per nucleus• contains RNA and proteins• not membrane delimited• functions to form the granular “subunits” of ribosomes


• molecules attach to cell-surface receptors concentrated in clathrin-coated pits

• receptor binding induces invagination

• also ATP-dependent and involves recruitment of actin and myosin

Receptor-mediated endocytosis:

Figure 2-11


Digestion of Substances in Pinocytotic or Phagocytic Vesicles

Figure 2-12

Step 1. • Carbohydrates are converted into glucose• Proteins are converted into amino acids • Fats are converted into fatty acids

Step 2. • Glucose, AA, and FA are processed into AcetylCoA

Step 3. • AcetylCoA reacts with O2 to produce ATP

A maximum of 38 molecules of ATP are formed per molecule of glucose degraded.

ATP production

(More in Chapter 67)

The Use of ATP for Cellular Function

1. Membrane transport2. Synthesis of

chemical compounds

3. Mechanical work

• under “standard” conditions G° is only -7.3 kcal/mole • ATP concentration is ~10x that of ADP, the G is -12 kcal/mole

Figure 2-15


The CytoskeletonIntermediate Filaments:

Microtubules:

Thin Filaments:

Thick Filaments:

• Comprised of cell-specific fibrillar monomers (e.g. vimentin, neurofilament proteins, keratins, nuclear lamins)

• Heterodimers of andtubulin• Make up spindle fibers, core of axoneme structure

• F-Actin• Make up “stress fibers” in non-muscle cells

• Myosin (types I and II)• Together with actin support cellular locomotion and subcellular transport

Cilia and Ciliary Movements:

• Each cilium is an outgrowth of the basal body and is covered by an outcropping of the plasma membrane.

• Occurs only on the inside surfaces of the human airway and fallopian tubes

• Each cilium is comprised of 11 microtubules

• 9 double tubules• 2 single tubules axoneme

Figure 2-17

• Ciliary movement is ATP-dependent (also requires Ca2+ and Mg2+)



Ameboid Locomotion:

• continual endocytosis at the “tail”and exocytosis at the leading edge of the pseudopodium

• attachment of the pseudopodium is facilitated by receptor proteins carried by vesicles

• forward movement results through interaction of actin and myosin (ATP-dependent)

Figure 2-16


Cell movement is influenced by chemical substances…

high concentration(positive)

Low concentration(negative)

Chemotaxis

U N I T I

Textbook of Medical Physiology, 11th Edition

GUYTON & HALL


Chapter 3:Genetic Control of Protein Synthesis,Cell Function, and Cell Reproduction

Slides by John E. Hall, Ph.D. and Louise C. Nuttle, Ph.D.


DNA (genes)

RNA

Proteins

Cell function

Structural Enzymes

Central Dogma of Molecular Biology

Figure 3-2


Transcription:

Figure 3-7


Step 1. RNA polymerase binds to the promoter sequence.

Step 2. The RNA polymerase temporarily “unwinds” the DNA double helix.

Step 3. The polymerase “reads” the DNA strand and adds complementary RNA molecules to the DNA template.

Step 4. “Activated” RNA molecules react with the growing end of the RNA strand and are added (3’ end).

Step 5. Transcription ends when the RNA polymerase reaches a chain terminating sequence, releasing both the polymerase and the RNA strand.

Overview:


Messenger RNA:

• complementary in sequence to the DNA coding strand

• 100’s to 1000’s of nucleotides per strand

• organized in codons - triplet bases - each codon “codes” for one amino acid (AA)- each AA - except met- is coded for by multiple codons- start codon: AUG (specific for met)- stop codons: UAA, UAG, UGA


DNA (genes)

RNA

Proteins

Structural Enzymes

Cell function

The Process of Translation

nuclear envelope

plasma membrane

DNA

NUCLEUS

DNA TRANSCRIPTION

RNA

RNA SPLICING

RNA TRANSPORT

ribosomesTRANSLATION OF MESSENGER RNA

protein

CYTOSOL


Transfer RNA• acts as a carrier molecule during protein synthesis• each transfer RNA (tRNA) combines with one AA

• each tRNA recognizes a specific codon by way of a complementary anticodon on the tRNA molecule

Figure 3-9


Polyribosomes: multiple ribosomes can simultaneously translate a single mRNA

Figure 3-11

Ribosomes


Chemical Events in Protein Formation

Figure 3-11


• small ribosomal subunit and initiator tRNA (Met) complex binds to 5’end of an mRNA chain

• this complex moves along mRNA molecule until it encounters a start codon (AUG)

• initiation factors dissociate and large ribosomal subunit binds

Overview :Protein Formation

Phase 1: Initiation


• AA-tRNA binds to the ribosomal A-site

• peptidyl transferase joins the tRNA at the P-site to the AA linked to the tRNA at the A-site with a peptide bond

• the new peptidyl-tRNA is translocated from the A-site to the P-site

Phase 2: Elongation



• Release factor binds to the stop codon.

• Completed polypeptide is released.

• Ribosome dissociates into its 2 subunits.

Phase 3: Termination



DNA (genes)

RNA

Proteins

Structural Enzymes

Cell function

transcriptionprocessingtransport to cytosol

translationmRNA stability

protein activity

Control of Genetic Function and Biochemical Activity


Genomics: the large-scale study of the genome

• Recent estimates suggest ~ 30,000 genes

• Humans are 99.8% identical at the genome level, 99.999% identical in the coding regions

Genomics


best guess...

identify a gene

determine nucleic acid sequence (sequence homology?)

determine amino acid sequence (fold homology?)

Bioinformatics


Proteomics: the large-scale analysis of proteins (i.e. the proteome)

• “Proteome” describes the protein composition of a cell

• approximately 10,000 proteins per cell, or ~15% of total possible gene products

Genome Proteome

Proteomics


The Operon: a procaryote model

• series of genes and their shared regulatory elements

• gene products contribute to a common process

Transcriptional Control:

Figure 3-12


• sequences called “repressor operators” bind repressor proteins

• binding interferes with the ability of the RNA polymerase to bind to the promoter

NO TRANSCRIPTION

Negative Regulation


• so-called “activator operators” bind activator proteins

• binding facilitates the association of the RNA polymerase with the promoter

ENHANCED TRANSCRIPTION

Positive Regulation


Life Cycle of the Cell: M phase:

• mitosis• cytokinesis

Interphase (>95%):• G1 phase• S phase (DNA synthesis)• G2 phase

Genetic Control of Cell Reproduction

Cells that cease

division

M(mitosis)

G1(Gap 1)

G2(Gap 2)

S phase(DNA synthesis)

EUKARYOTIC CELL CYCLE


• switched on by the cytoplasmic S-phase activator

• Replication is initiated at replication origin and proceeds in both directions.

• Entire genome is replicated once - further replication is blocked

DNA Replication: S phase

• involves DNA polymerase and other proteins that function to unwind and stabilize the DNA and “prime” DNA replication of the “lagging” strand.


• nucleotides are always added to the 3’ end (DNA and RNA)

• formation of Okazaki fragments on lagging strand

• “new” DNA is proofread by DNA polymerase

• repairs are made and gaps filled by DNA ligase

DNA Replication: S phase


• “New” DNA helices associate with histones to form chromosomes

• The two chromosomes remain temporarily attached at the centromere.

• Together, these chromosomes are called chromatids.

Chromosomes and Their Replication


Mitosis: M phase

1. Assembly of the mitotic apparatus

2. Prophase (A,B,C) 3. Prometaphase (D)4. Metaphase (E)5. Anaphase (F)6. Telophase (G, H)

Figure 3-13

Stages of Cell Reproduction


Control of Cell Growth

RAPID: bone marrow, skin, intestinal epithelia

SLOW/NEVER: smooth muscle, neurons, striated muscle

What determines the rate of cell growth?• growth factors• contact inhibition• cellular secretions (negative feedback)


Cell Differentiation

• changes in physical and functional properties of cells as they proliferate

• results not from the loss of genes but from the selective repression/expression of specific genes

• development occurs in large part as a result of “inductions,” one part of the body affecting another

Different from reproduction ...


Cancer

Caused in all or almost all cases by the mutation or abnormal activation of genes that encode proteins that control cell growth and/or mitosis

• Proto-oncogenes: the “normal” genes• Oncogenes: the “abnormal” gene• Antioncogenes: genes whose product suppress the

activation of oncogenes

Not all mutations lead to cancer!

Dysregulation of cell growth


What causes these mutations?

• Ionizing radiation: disrupts DNA strands

• Chemicals: “carcinogens”

• Physical irritants: e.g., abrasion of the intestinal lining

• Hereditary “tendencies”: e.g., some breast cancer

• Viruses: so-called “tumor viruses” (particularly retroviruses)


Q: Why does cancer kill?

A: Cancer cells compete successfully with normal cells

for limited nutrients

2. the cell and its function and genetic control of protein

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