 M phase (mitosis) is the time in which the cell

divides to form 2 daughter cells

 Interphase the time between 2 cell divisions or

mitoses.
 G1 phase (gap 1) is a period of cellular growth
preceding DNA synthesis
 S phase (DNA synthesis) is the period of time during
which DNA replication occurs
 G2 phase (gap 2) is a period of cellular growth after
DNA synthesis but preceding mitosis
Drug chemotherapeutic

NUCLEOTIDE STRUCTURE AND NOMENCLATURE

The pentose is ribose, the nucleic acid is RNA (ribonucleic

acid)

The pentose is deoxyribose, the nucleic acid is DNA

(deoxyribonucleic acid)
Nucleoside= Nitrogen Base + Sugar

Nucleotide= Nitrogen Base + Sugar

+ gốc phosphates
  Must be written 5′-TCAG-3′ or TCAG( DNA)  Nếu đề không ghi.

3 cách đọc:

1. 3′-GACT-5′

2. pTpCpApG  positions of phosphates

3. dTdCdAdG  d” (deoxy)

 DNA is generally double-stranded (dsDNA) and RNA is generally single-stranded (ssRNA)

Such renaturation or annealing of
complementary DNA strands is an
important step in probing a
Southern blot and in performing
the polymerase chain reaction
  Euchromatin: opened and available for gene
expression

 Heterochromatin: highly condensed and
associated with areas of the chromosomes that
are not expressed

• Polymerases: synthesize nucleic acids by forming phosphodiester (PDE) bonds.

• Nucleases are enzymes that hydrolyze PDE bonds.

– Exonucleases remove nucleotides from the 5′ or the 3′ end of a nucleic acid.

– Endonucleases cut within the nucleic acid and release nucleic acid fragments
Red circle is telomeres

longthen in the germ cell and

tumor cell

Telomeresshorthen

Apostosis

Shorthen: ngắn đi

Longthen: dài ra
Leading Strand Synthesis (Continuous)
 Lagging Strand Synthesis (Discontinuous)

2. DNA polymerases α and δ extend the primer,

moving away from the replication fork (Lagging

strand synthesis).

3. Synthesis stops when DNA polymerase

encounters the primer of the leading strand on the

other side of the diagram (not shown), or the primer

of the previous (Okazaki) fragment.

4. As helicase opens more of the replication fork, a

third Okazaki fragment will be added.

5. RNase H (5' exoribonuclease activity) digests the

RNA primer from fragment.

Topoisomerase relax the tension in
replication DNA cut and remove 6. DNA ligase connects fragments 1 and 2 by
Decrease in replication
making a phosphodiester bond.

7. DNA gyrase: overwound kết dính

Quinolones and fluoroquinolones Treatment of gonorrhea and upper and lower urinary

inhibit DNA gyrase tract infections

• Levofloxacin

• Ciprofloxacin

• Moxifloxacin
Autoimmune disease:
Scleroderma
Damage Cause Recognition/ Repair
Excision Enzyme Enzymes

Thymine UV radiation Excision endonuclease

dimers (G1)
= excinuclease enzyme

 Deficient in Xeroderma
Pigmentosum(XP)
Mismatched DNA replication A mutation one of two genes:
base (G2) errors
1. hMSH2
2. hMLH1
DNA polymerase
 Hereditary nonpolyposis
DNA ligase
colorectal cancer—HNPCC

(Lynch syndrome)

 microsatellite instability
may be used as a diagnostic
tool
Cytosine Spontaneous/ heat Uracil glycosylase
deamination G1
AP endonuclease

Repair of Thymine Dimers

Heterogeneous nuclear RNA (hnRNA or pre-mRNA): found only in Start signals: promoters
the nucleus of eukaryotic cells
Stop signals: terminators
 Formed during its posttranscriptional processing

Small nuclear RNA (snRNA), which is also only found in the nucleus
of eukaryotes.

 Participate in splicing (removal of introns) mRNA.

The RNA product is

 Antiparallel
 Complementary

With the template.

Promoter not transcribed

 RNA polymerase start at +1

  Coding strand the same mRNA, only chage T=U

 Coding strand always 5’3’ if not write the direction

Expression of a Prokaryotic Protein Coding Gen

 Polycistronic:
many gene have
one promoter
 No intron
 Trancription(TC)
and
Translation(TL)
are coupled

 Shine-Dalgarno sequence: initiation of translation and tRNA attaching

Expression of a Prokaryotic Protein Coding Gen

Expression of a Eukaryotic Protein Coding Gen

 Always Monocistronic( Each gene has its own promoter)

 Extron ( Expressed part) + Intron ( Intervening part)
 Trancription(TC) and Translation(TL) not coupled
The primary transcript is spliced differently to produce two or more variants
of a protein from the same gene Alternative splicing(detected by
Northern blot)

Variants of the muscle proteins tropomyosin and troponin T are produced.

The synthesis of membrane-bound immunoglobulins by unstimulated B

lymphocytes, as opposed to secreted immunoglobulins by antigen-stimulated
B lymphocytes
RIBOSOMES 70S, 50S, 30S: odd

80S, 60S, 40S: even

TRANSFER RNA (tRNA)

 Acceptor+ A.axit
 Anticodon+Codon

Aminoacyl-tRNA synthetase

 Important
Important Points About Transcription and RNA Processing
Prokaryotic Prokaryotic Eukaryotic
May be polycistronic Always monocistronic

Genes: continuous Genes: exons and introns

Very little spacer (noncoding) Large spacer (noncoding) DNA

Gene regions
DNA between genes between genes

1. RNA polymerase I: rRNA

2. RNA polymerase II: mRNA;
RNA polymerase
snRNA
3. RNA polymerase III: tRNA,
Core enzyme: α2ββ′ 5S RNA highyeih (Only)
Promoter (–10) TATAAT, Promoter (–25) TATA and (–70)
(35)sequence CAAT
Initiation of
transcription
Sigma required to recognize Transcription factors (TFIID)

promoter bind promoter

Template read 3′ to 5′; mRNA synthesized 5′ to 3′;

mRNA synthesis gene sequence specifed from coding strand 5′ to 3′

transcription begins at +1 base

Termination of Stem and loop + UUUUU Not well characterized

transcription Stem and loop + rho factor

Relationship of RNA RNA is antiparallel + complementary to DNA template strand;

transcript to DNA RNA is identical (except U substitutes for T) to DNA coding strand
Posttranscriptional None In nucleus:
processing of hnRNA 5′ cap (7-MeG)
(pre-mRNA)
3′ tail (poly-A sequence)
 Removal of introns from pre-
 RNA

• Alternative splicing yields

variants of protein product
70S (30S and 50S)
Ribosomes 80S (40S and 60S)
rRNA and protein
rRNA and protein
Cloverleaf( cỏ 3 lá) secondary structure
• Acceptor arm (CCA) carries amino acid
tRNA
• Anticodon arm: anticodon complementary and antiparallel to
codon in mRNA
 Alpha- Thalasemia

 Beta- Thalasemia
 Gaucher diseaser
 Tay-Sachs

 Hungtinton disease( CAG)

 Muscular trophy( CAG)
 Myotonic dystrophy
 Fragile X syndrom
 Friedreich’s ataxia

TRANSLATION
(PROTEIN
SYNTHESIS)
Peptide bond is very strong
Steps of Translation
The process of protein synthesis occurs in 3 stages: initiation( IF), elongation(EF) , and
termination(TF)

 Aminoglycosis inhibits 30S inhibits IF ( Ototoxicity, Nephrotoxicity)

 Tetracyclin inhibits 30S inhibits A position inhibits EF
 P : posterior, A: anterior

 Chloramphenicol: inhibits 50S Block peptidyl transferase Inhibits EF

Peptidyl transferase: form Peptide bond
 Macrolides: inhibits 50S Inhibits EF

Anticipation used to describe a disease that, from generation to generation, shows a decrease
in the age of onset and an increase in the severity of symptoms
Toxin+ Mech block eEF-2 decrease Aa synthesis Use Aa for bacteria synthesis

PROTEIN FOLDING AND SUBUNIT ASSEMBLY

Primary—sequence of amino acids

Secondary—folding of the amino acid chain

Tertiary—3-dimensional shapes
Quaternary—in proteins such as hemoglobin Sub-unit

Degradation of Misfolded Proteins by Proteasomes

Degradation of Misfolded Proteins by Proteasomes

1. N-terminal hydrophobic signal sequence used to ensure translation on the RER
 IN ADDITION TO DISULFIDE BOND FORMATION WHILE PROTEINS ARE FOLDING, OTHER
COVALENT MODIFICATIONS INCLUDE :

• Glycosylation: addition of oligosaccharide as proteins pass through the ER

and Golgi apparatus
• Proteolysis: cleavage of peptide bonds to remodel proteins and activate them
(proinsulin, trypsinogen, prothrombin)
• Phosphorylation: addition of phosphate by protein kinases

• γ-Carboxylation: produces Ca2+ binding sites

• Prenylation: addition of farnesyl or geranylgeranyl lipid groups to certain
membrane-associated proteins

Gamma-carboxylation: 6 Protein( 2-7-

9-10)= Clotting + Protein C and Protein
S= Anticoaglutant
Ehlers-Danlos syndromes:

 Ruptures areurysm in Willis Cycle( Berry)

 Subarachnoid hemorrhage

Menkes disease( Ehlers-Danlos syndromes type IX): differences Wilson disease

Mutations in the gene ATP7A

 Copper( Cu2+) absorbed into the mucosal cell, but cannot be transported into the bloodstream.

Severe copper deficiency + all Copper-Requiring enzymes will be affected

Transcription factors contain at least 2 recognizable domains:

1. A DNA-binding domain

– Zinc fingers (steroid hormone receptors)

– Leucine zippers (cAMP-dependent transcription factor)

– Helix-loop-helix

– Helix-turn-helix (homeodomain proteins encoded by homeotic/ homeobox genes)

2. An activation domain
Important Specifc Transcription Factors
  Glucagon

secreted in response to hypoglycemia

functioning via a membrane-associated receptor that increases cAMP concentration

 Cortisol

secreted in response to stress acts through an intracellular receptor( a Zinc-finger= steroid

receptors)

Control Poin Example

Inactivation of

1. Specifc chromosomes One X chromosome in each cell of a woman is inactivated

2. Chromosomal regions during  Heterochromatin (Barr bodies)

development
Local chromatin-modifying Acetylation of histones increases gene expression (many

activities genes)
 Methylation of DNA silences genes in genetic imprinting

 Prader-Willi and Angelman syndromes

Chromosome 15:normally expressed only from the

paternal, not the maternal

 If one inherits a paternal chromosome in which

this region has been deleted, Prader-Willi

syndrome results:

• Childhood obesity and hyperphagia

• Hypogonadotrophic hypogonadism

• Small hands and feet

Paternal: daddy
• Mental retardation
Maternal: mom
• Hypotoni
Oncogenes are present in multiple copies:

 erbB amplifed in certain breast cancers

Gene amplification
Dihydrofolate reductase genes are amplifed in some tumors

 Leading to drug resistance

Steroid hormone receptors, CREB, and homeodomain
Specifc transcription factors
proteins
Alternative splicing of mRNA in the production of
Processing mRNA
membrane-bound vs. secreted antibodies

Rate of translation Heme increases the initiation of β-globin translation

Protein modification( hoạt hóa) Proinsulin is cleaved to form active insulin

Protein degradation rate ALA synthase has a half-life of 1 hour in the hepatocyte
BLOTTING TECHNIQUES

 Detect and visualize specifc DNA, RNA, and protein among complex mixtures
DNA
Restriction endonuclease
DNA Fragment( restriction fragments) DNA

Identifcation and characterization of the genes involved in numerous inherited

diseases

Notes:

RNA= small

Protein= denature

 Easy analyze
 DNA restriction
fragments are
analyzed on a
Southern blot.

DNA probes are

radioactively labeled
single-stranded DNA
molecules
DNA probes used to
selectively detect
DNA fragments
 Tạo ra probes để bổ sung với đoạn DNA cần
tìm.  Important
part of
analyzing any
blot because
the only bands
that will appear
on the final
autoradiogram
are those to
which the
probe has
hybridized
Southern Blots and Restriction Fragment Phenotypically:
Length Polymorphisms (RFLPs) kiểu hình

Tandem repeat:
đoạn lặp lại ngẫu
nhiên

 Variable from
 person to
person

Đỉnh(-): Largest

Đáy(+): Smallest

AA homozygous for
A

AB heterozygous

BB homozygous for
B

Màu đậm:
homozygous

 Tạo 2 copies
AA,BB giống
nhau nên đậm

 The blot on the right is correct Màu nhạt:

heterozygous

 Tạo 2 copies
khác nhau ,
chia ra nên
nhạt
Northern Blots: genes expressed extracted from: trích xuất
 Analyze RNA extracted from a tissue and are typically used to từ
determine which genes are being expressed
 Fragile X
Syndrome

The one gene involved,

FMR1  Long arm of the
X chromosome
  Inherited mental
retardation

Pattern of gene
expression= Gene
expression profling=
Microarrays( Vi mô)

Tissues express the FMR1 gene involved in fragile X syndrome.

Western Blots : Protein

 One important application of Western blotting is to detect the

presence of
antibodies to the HIV virus in HIV testing
POLYMERASE CHAIN REACTION (PCR) The nucleotide sequence
The polymerase chain reaction (PCR) is a technique in which a bordering (flanking)

selected region of a chromosome can be amplifed more than a

This process is repeated for
million-fold within a few hours.
approximately 20 cycles,

producing over a million double-

stranded copies of the target

sequence.

The PCR used for:

• Comparing DNA samples in

forensic cases

• Paternity testing

• Direct mutation testing

• Diagnosing bacterial and viral

infections

• HIV testing when antibody

tests are uninformative

(importantly, infants whose

 mothers are HIV- positive)

Agarose gel electrophoresis of PCR products Electrophoresis: điện di

If the known mutation changes the length of the gene (e.g.,
microsatellite
repeats)

 Detected in the PCR-amplifed DNA by electrophoresis on

agarose gel
Consistent with: tương
ứng với

Answer: Yes, the results are consistent with Huntington disease( CAG
repeat)
In comparison with the normal control PCR products, one of the
patient’s PCR products (170 bp) is well out of the normal range.

 a Triplet repeat expansion in that allele of the huntingtin gene.

The 2 bands from the control are 95 base pairs and 101 base pairs, a
difference of 2 triplet repeats.
The patient sample shows a 104 base pair band, a difference of one
triplet repeat from
the larger control band.
170-101=69  23 triplet repeats.

Genetic Fingerprinting Using PCR Amplifcation of Microsatellite PCR amplifcation of

Sequences repetitive sequences
 Vân tay DNA
1. VNTR
2. STR sequences
 Used for genetic
fngerprinting.
Paternity testing using PCR amplification of microsatellite
sequences
Case 1: May be the father: he shares a band with the child.

 We cannot be certain, because many other men in the population

could have this same band.
 Matches are required at several different loci to indicate with
high probability that a tested male is the father.

Case 2: Cannot be the father, his bands is not shared with the child.

Probability: xác xuất

Loci( N plural) Locus: 1 điểm hay vị trí trừ tượng

PCR in Direct Mutation Testing DNA Sequencin

If the mutation(s) causing a specific disease is known, the loci involved
Đọc :5’CTTGGAACTGTA 3’
can be amplified with a PCR and further analyzed to determine whether
the mutation(s) is present.

1. Mutations causing a length difference gel electrophoresis +

length difference in the PCR product.
2. Mutations causing a sequence difference  Testing the PCR
products with ASOs.
 Cách đọc

Smallest largest

PositiveNegative

PCR in HIV Testing(Western blot) A PCR for the HIV provirus

Te enzyme-linked immunosorbent assay (ELISA)  used to screen has 2 important
individuals for antibodies to the HIV virus.
advantages over the
 The test has high sensitivity but lower specificity
ELISA/ Western blot:
 ELISA/Western blot is not useful and PCR is the test of choice to
• Is positive much earlier
detect HIV infection.
after infection
HIV testing in newborns whose mothers are HIV positive (will
always be positive in ELISA/ Western blot) • Does not rely on an

Early testing afer known exposure to HIV-positive antibody response by the

blood(needlesticks)
individual
Reverse Transcriptase PCR (RT-PCR)( Northern blot) The RT-PCR is used to
An RT-PCR detects and can quantify a specific RNA rather than DNA measure the
Measuring viral load in AIDS patients
concentration of active

circulating virus in the

blood of an AIDS patient

(viral load).

The test can be used to

1. Monitor the status

 of infection

2. The infection’s

response to

antiviral drugs.
Classifed as hydrophobic or hydrophilic Only 20 are used as
building blocks of
Hydrophobic side chains are in the interior of the molecule where
proteins in humans
they are protected from water

Hydrophilic side chains are on the surface.

Alpha-cacbon(C2)
Lysine, Arginine tích điện dương(+2)> Histidine(+1)

The Hydrophobic Amino Acids The Hydrophilic Amino Acids

• Glycine dominates collagen

•Alanine: gluconeogenesis
•Lysine + Vita C form Hydroxylysine
•Phenylalanine and Tyrosine: precursors for
•Arginine: percursor for Urea
catecholamines.
•Aspartate: Urea cycle

•Phenylalanine : defectes PKU: phenylketouria •Glutamate: GABA

• Tryptophan: form serotonin and niacin. • Serine, Threonine(-OH): sites for O-linked
• Valine, Leucine, Isoleucine is abnormal in glycosylation Golgi apparatus

maple syrup urine disease • Asparagine(-NH2): site for N-linked

• Proline is a secondary amineOnly Colagen glycosylation Endoplasmic reticulum

• Cysteine contains sulfur, form disulfide

Aliphatic : không thơm( không vòng) ,
bondsstabilize the shape (tertiary structure).
Aromatic: thơm( vòng)
Destroying bonds denatures proteins

• Methionine, another sulfur-containing

amino acid, is part of S-adenosylmethionine
(SAM) A methyl donor

•Glutamine: carrier of blood ammonia

Hemoglobinopathy

In sickle cell anemia, there is a substitution of valine for

glutamate at position 6 in Hb, meaning that the HbS  one less
negative charge overall compared with HbA.

In HbC, there is a substitution of lysine for glutamate at

position 6, meaning that HbC  two additional positive charges
compared with HbA.

a substitution: thay thế

PROTEIN TURNOVER AND AMINO ACID NUTRITION Essential Amino Acids

10 amino acids that cannot

Protein turnover replaced older proteins, Mutation
be synthesized must be
proteinDifferent types of proteins have very different turnover
provided from dietary
rates sources

Arginine important in positive

Occurs in 2 cellular locations:
nitrogen balance Synthesis of
• Lysosomal proteases digest endocytosed proteins.
histones in the growing cell
• Large cytoplasmic complexes (or proteasomes) digest older

or abnormal proteins (called ubiquitin)

 Nitrogen Balance Don’t confuse kwashiorkor
with
Amount of nitrogen incorporated into the body each day = marasmus.
Amount excreted.
Marasmus is a chronic
deficiency of calories +
Negative nitrogen balance occurs when nitrogen loss exceeds
protein Child <1 year
incorporation. It old, Not edema
is associated with:
Kwashiorkor: is a form of
• Protein malnutrition (kwashiorkor) severe protein
malnutrition( deficiency
• Dietary deficiency of even 1 essential amino acid
protein)  edema
• Starvation

• Uncontrolled diabetes
Malnutrition: suy dinh
• Infection
dưỡng

Positive nitrogen balance occurs when the amount of nitrogen

incorporated

exceeds the amount excreted. It is associated with:

• Growth Children, Newborn

• Pregnancy

• Convalescence (recovery phase of injury or surgery) Recovery

• Recovery from condition associated with negative nitrogen

balance

BIOCHEMICAL REACTIONS ∆G: Amount of energy

released or required per mole
Thermodynamically : nhiệt động
of reactant( Vốn có) enzym
not affect

The rate of the reaction is

determined by ∆G‡ the energy
required to initiate the
reaction( từ môi trường)
Enzym affect
Michaelis-Menten Equationthe rate of the reaction

 V depends on the concentration of the enzyme [E]

+ the substrate [S] which forms product [P]

 Vmax is the maximum rate possible to achieve with a

given amount of enzyme Increasing the [E]=

Increase Vmax.

 Km =the substrate concentration required to produce Hyperpol

e
1/2Vmax  The Km cannot be altered by changing

[S] or [E]

 The higher Km = lower afinity for its substrate

 The lower Km= higher afinity for its substrate

Lineweaver-Burk Equation form of Michaelis-Menten

equation

Đặt

1/V= Y

1/[S]= X

 Y= X+

Nếu X=0 Y=
 Nếu Y=0 Y=

Inhibitors and Activators Competitive inhibitors

resemble(giống) the substrate
Many drugs are competitive inhibitors of key enzymes in
Binding to the active site of the
pathways.
enzyme.
• The statin drugs (lovastatin, simvastatin)
competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme Noncompetitive inhibitors
A (HMG CoA) reductase used to control blood cholesterol not bind at the active site Bind
• Methotrexate, an antineoplastic drug competitively to regulatory sites on the
inhibits dihydrofolate reductase  Anti DNA replication enzyme.
during S phase.

Cooperative Enzyme Kinetics Methanol poisoning is treated

with ethanol
Allosteric enzymes the shape changes  Induced or
administration.
stabilized by binding substrates, inhibitors, and activators.
Ethanol having a much lower
Km for
the enzyme compared with
methanol.
 Prevent Methanol converted
to formaldehyde  toxic + not
 metabolized further.

Transport Kinetics Km, Vmax apply to enzymes

transporters in membranes
Few hormones bind to receptors on the cell Produces them (autoregulation or autocrine function)

Hormones are more commonly acting on some other cell:

1. Close( paracrine): short half-life (prostaglandin, neurotransmitters)

2. Distant site (telecrine): longer half-life( the endocrine,gastrointestinal (GI) hormones
Water-Soluble Lipid-Soluble Water-soluble hormones
Receptor in cell membrane Receptor inside cell Zin-Finger  Not entering the
protein cytoplasm
Second messengers often Hormone–receptor complex binds
involved hormone response elements (HRE) Neet second
Protein kinases activated of enhancer regions in DNA messenger systems
Protein phosphorylation to modify — activate protein kinase
activity of enzymes (requires
minutes)
Control of gene expression Control of gene expression
through proteins (requires hours)
 cAMP response element
binding (CREB) protein (requires
hours)
Examples: Examples:
• Insulin • Steroids
• Glucagon • Calcitriol= 1.25-dihyroxy-D3
• Catecholamines • Thyroxines
• Retinoic acid
Protein Kinases A protein kinase is
Water-Soluble
an
enzymephosphor
ylates other
proteins, changing
their activity

Enzym Protein Kinase

cAMP PKA

cGMP PKG

DAG,IP3, Ca PKC

Water-soluble hormones + Intrinsic( nội tại) protein kinase activity

(tyrosine kinases). No second messenger required for protein kinase

activation.

Example: The insulin receptor

Water-Soluble

Phosphorylation:

Enzymesrapidly increase or decrease

activity( Minutes)

Gene regulatory protein

Control gene expression (several hours)

G protein
Water-Soluble
 Cyclic AMP (cAMP) and phosphatidylinositol bisphosphate (PIP2) Water-Soluble

Hormone binds receptor

• Trimeric G protein in membrane engaged

• adenylate cyclase, phospholipase activated

• Second messenger generated

• Protein kinase activated

• Protein phosphorylation (minutes) and gene expression (hours)

cAMP, cGMP slowly degraded by a class of enzymes: Phosphodiesterases (PDEs).

Atrial natriuretic factor (ANF) produced by

vasodilators
cells in the atrium of the heart response
to distension

 Binds ANF receptor in vascular

 smooth muscle + the kidney.
 Causes relaxation of vascular smooth muscle, resulting in vasodilation.

 Promotes sodium and water excretion in the kidney.

Nitric oxide (NO) synthesized by vascular endothelium

 Activating the enzyme: soluble guanylate cyclase

Second messengers cAMP, cGMP slowly degraded by enzymes called phosphodiesterases

(PDEs)

Water-Soluble
The Insulin Receptor: A Tyrosine Kinase
Water-Soluble

increase GLUT-4 in the

membrane

Ras gene encoded

Water-Soluble

(+)P Glycogenolysis

(-)P Glycogen synthesis

G PROTEINS IN SIGNAL TRANSDUCTION( truyền) Water-Soluble

G proteins (GTP-binding):

1. Trimeric G proteins include Gs, Gi, Gq,

2. Gt (transducin)

 7-helix membrane-spanning: receptor

p21ras G protein is monomeric

pertussis= whooping cough: ho gà

Bacterial exotoxins are enzymes
Vita Niacin

Attach the adenosine diphosphate

(ADP)-ribose residue of NAD to Gα

subunits

 Call: ADP ribosylation

Water-Soluble Vitamins

Vitamin or
Enzyme Pathway Deficiency
Coenzyme
MCC= Most Common Cause:
excessive consumption of raw eggs
(contain Avidin, a biotin-binding
protein tight bind)

Pyruvate Gluconeogenesi
carboxylase s
Acetyl
Fatty acid
Biotin synthesis

Biotinyl-lysine CoA carboxylase

Odd-carbon
Propionyl CoA fatty acids, Val,
carboxylase Met, Ile, Thr

Alopecia (hair loss): rụng tóc

Bowel inflammation
Muscle pain
Thiamine (B1) Pyruvate PDH MCC: alcoholism (inhibit absorption)
dehydrogenase
Thiamine TCA cycle Wernicke (ataxia, nystagmus, ophthal-
pyrophosphate
α-Ketoglutarate moplegia)
dehydrogenase HMP shunt
Korsakoff (confabulation, psychosis)
Transketolase Metabolism of
 Wet beri-beri (high-output cardiac
failure, fluid retention, vascular leak)
valine
Branched chain Cardiac Problem
isoleucine and
ketoacid dehy
leucine
drogenase Dry beri-beri (peripheral
neuropathy)Neurological Problem
Pellagra: diarrhea, dementia,

Niacin (B3) dermatitis If not treated: death

PellagraAlso cause deficiency of
Dehydrogenases Many
NAD(H) tryptophan (corn is low in tryptophan)
NADP(H) High-dose niacin used to treat
hyperlipidemia
MCC: alcoholism and pregnancy (body
Thymidylate stores depleted in 3 months),
synthase hemodialysis thận nhân tạo
Thymidine
Folic acid (pyrimidine) Homocystinemia with risk of deep vein
synthesis thrombosis and atherosclerosis

THF Enzymes in Megaloblastic (macrocytic) anemia

purine synthesis Purine synthesis thiếu máu hồng cầu to
need
not be memorized Deficiency in early pregnancy causes
neural tube defects in fetus
MCC: pernicious anemia( thiếu máu ác
tính). Terminal c resection
Cyanocobalami
n (B12) Crohn disease
Homocysteine Methionine, SAM
Chronic pancreatitis
methyltransferase
Nutrional: vegar
Odd-carbon
Methyl Infection with D. latum
cobalamin Methylmalonyl fatty acids, Val,
CoA mutase Met, Ile, Thr
Deoxyadenosyl Megaloblastic (macrocytic) anemia
cobalamin

Progressive peripheral neuropathy

Pyridoxine (B6) Aminotransferase Protein MCC: Isoniazid therapy(INH)
s (transaminase): catabolism
Pyridoxal-P
(PLP) AST (GOT), ALT Sideroblastic anemia (thiếu máu
(GPT) nguyên hồng cầu)
 Cheilosis or stomatitis (cracking or
scaling of lip borders and corners of
δ-Aminolevulinate Heme synthesis
the mouth)
synthase

Convulsions
Corneal neovascularization
Cheilosis or stomatitis (cracking or
scaling of lip borders and corners of
the mouth)

Riboflavin (B2)

FAD(H2)
Dehydrogenases Many
 Light
sensitive

Magenta-colored tongue
Ascorbate (C) Prolyl and lysyl Collagen MCC: diet deficient in citrus fruits and
hydroxylases synthesis green vegetables
 No
enzyme
form Dopamine Catecholamine Scurvy: poor wound healing, easy
hydroxylase synthesis bruising (perifollicular( nang long)
hemorrhage)
Dopamine
hydroxylase Absorption of
iron in GI tract

Hepatic
synthesis of bile
 Purpura, and ecchymoses are seen most
commonly
bleeding gums, increased bleeding
time, painful glossitis, anemia

Vitamin C is necessary as a cofactor by

proline and lysine hydroxylases in

acids collagen synthesis.

In scurvyNot hydroxylatedCollagen

fibers less stable than normal

Overdoses:

Pantothenic Fatty acid Fatty acid Rare Not care

acid
synthase metabolism
 Fatty acyl CoA
synthetase

Pyruvate PDH
CoA
dehydrogenase TCA cycle

α-Ketoglutarate
dehydrogenase

Lipid-Soluble Vitamins

Vitamin Important Functions

D In response to hypocalcemia, helps normalize serum

calcium levels

(cholecalciferol)
Vitamin D deficiency is caused by

insufficient sunlight, inadequate( đầy đủ)

fortified foods (milk), or end-stage renal

disease (renal osteodystrophy).

Symptoms:

• Bone demineralization

• Rickets (children): còi xương

• Osteomalacia (adults): Nhuyễn

sươngMatrix not present different

osteoporosis( Loãng xương)

Bisphosphonates( ibandronate, risedronate, alendronate)

Treatment of osteoporosis( loãng xương)

Inhibiting osteoclast action and resorption of bone

 Increase in bone mineral density (BMD)

 Strengthening of bone + decrease in fractures

Retinoic acid, retinol actgrowth regulators, especially
A (carotene)
in epithelium

Vitamin A deficiency: caused by fat Retinal is important in rod( black and white) and

malabsorption or a fat-free diet. cone( color) cells for vision Not hormon

Stored in liver: Ito cell

Symptoms:

• Night blindness

• Keratinized squamous epithelia

• Xerophthalmia( khô giác mạc), Bitot

spots

 Sự gia tăng nồng độ keratin trong kết mạc

của mắt.

11-cis-Retinol + Opsin=Rhodopsin( Photoreceptor)

• Keratomalacia( nhuyễn giác mạc)

blindness

• Follicular hyperkeratosis: tăng sừng hóa

• Alopecia

Open when dark: Partical polarization  Rhodopsin active Outer

rod segment inner rob segement stimulate Glutamate Glutamate

+ Bipolar cell

 Inhibit the synaps: see nothing in the dark

Closed in light:  Rhodopsin active Phosphodiesterase Destroy

cGMP

 Na+, Ca2+ not coming in + Pump out ion = hyperpolarization

Glutamte not release + Bipolar cell

  The sensation + see( perceives) something in brain
K Carboxylation of glutamic acid residues in many

Ca2+-binding proteins

menaquinone(K2)Bacteria importantly coagulation factors II, VII, IX, and X, as

phytoquinone(K1)Plants well as protein C and protein S

Vitamin K deficiency include:

•Fat malabsorption (bile duct

occlusion)

• Prolonged treatment with broad-

spectrum( phổ rộng) antibiotics

(eliminate( loại bỏ) intestinal

bacteria that supply vitamin K)

• Breast-fed( bú mẹ) newborns (little

intestinal flora, breast milk very low

in vitamin K), especially in a home-

birth where a postnatal injection of

vitamin K may not be given

• Infants whose mothers have been

treated with certain

anticonvulsants(chống co giật)

during pregnancy such as phenytoin

(Dilantin)

Warfarin and dicumarol

Antagonize the γ-carboxylation

activity of vitamin KAffect

precoagulation factors
Anticoagulants

1. Prevent coagulation only in

vivo and cannot in vitro

2. 2–3 days full anticoagulant

activity

Heparin, Low molecular-weight

heparin Short-term anticoagulant

activity.
Antioxidant in the lipid phaseProtects membrane
E (α-tocopherol)
lipids from peroxidation

Vitamin E deficiency is caused by fat  High blood levels of vitamin E can cause

malabsorption or premature birth. hemorrhage in patients given Warfarin the

Symptoms:
same structure
• Hemolytic anemia

• Acanthocytosis: bệnh hồng cầu gai

• Peripheral neuropathy

• Ataxia

• Retinitis pigmentosum: viêm võng mạc sắc

tố
0-90

Anabolic and catabolic controlled at 3 important levels:

• Allosteric inhibitors and activators of rate-limiting enzymes Fast

• Control of gene expression by insulin and glucagon Slow

common metabolic
• Phosphorylation (glucagon) and dephosphorylation (insulin) of

rate-limiting enzymes  Fast

Energy is extracted from food via oxidation ,4 stages

1. Metabolic fuels are hydrolyzed in the gastrointestinal (GI) tract into monomeric building

blocks: glucose, amino acids, and fatty acids absorbed.

2. Building blocks degraded by various pathways in tissues to a common metabolic

intermediate: acetyl-CoA

3. Acetyl-CoA is aerobically oxidized to CO2 throught the citric acid cycle

4. Oxidative phosphorylation: energy from NADH and FADH 2

 Released via the electron transport chain (ETC)

 Used by an ATP synthase to produce ATP( requires O2) Not store ATP, Store

Cacbonate
Metabolic Profile of the Well-Fed (Absorptive) State

Blood glucose level rises and stimulates the release of insulin

3 major target tissues: liver, muscle, and adipose tissue

 Brain and red blood cells—are independent insulin

Prolonged Fast (Starvation)
Levels of glucagon and epinephrine are markedly elevated during starvation.
Lipolysis is rapid, resulting in excess acetyl-CoA that is used for ketone synthesis. Levels of both
lipids and ketones are therefore increased in the blood.
Muscle uses fatty acids as the major fuel, and the brain adapts to using ketones for some of its
energy.
After several weeks of fasting, the brain derives approximately 2/3 of its energy from ketones
and 1/3 from glucose. The shift from glucose to ketones as the major fuel diminishes( giảm dần)
the amount of protein that must be degraded to support gluconeogenesis. There is no “energy-
storage form” for protein because each protein has a specific function in the cell. Therefore, the
shift from using glucose to ketones during starvation spares protein, which is essential for these
other functions.
Red blood cells (and renal medullary cells) that have few, if any, mitochondria continue to be
dependent on glucose for their energy
Liver

Two major roles of the liver in fuel metabolism are to maintain a constant

level of blood glucose under a wide range of conditions and to

synthesize ketones when excess fatty acids are being oxidized

•In the well-fed state, the liver derives most of its energy from the oxidation

of excess amino acids

• Between meals and during prolonged fasts, the liver releases glucose into

the blood

Adipose Tissue

After a meal, the elevated insulin stimulates glucose uptake by adipose

tissue.

Insulin also stimulates fatty acid release from VLDL and chylomicron

triglyceride (triglyceride is also known as triacylglycerol).

• Lipoprotein lipase, an enzyme found in the capillary bed of adipose tissue, is

induced by insulin.

• The fatty acids that are released from lipoproteins are taken up by adipose

tissue and re-esterified to triglyceride for storage.

• The glycerol phosphate required for triglyceride synthesis comes from

glucose metabolized in the adipocyte

• Insulin is also very effective in suppressing the release of fatty acids from

adipose tissue.
• During the fasting state, the decrease in insulin and the increase in

epinephrine activate hormone-sensitive lipase in fat cells, allowing fatty acids

to be released into the circulation.

Skeletal Muscle

Resting muscle: The major fuels of skeletal muscle are glucose and fatty

acids

Active muscle: The major fuels of skeletal muscle are fatty acids and ketone

bodies

Cardiac Muscle

During fetal life, cardiac muscle primarily uses glucose as an energy source,

but in the postnatal period there is a major switch to β-oxidation of fatty

acids.Thus, in humans, fatty acids serve as the major fuel for cardiac

myocytes.

When ketones are present during prolonged fasting, they are also used. Thus,

not surprisingly, cardiac myocytes most closely parallel the skeletal muscle

during extended periods of exercise.

In patients with cardiac hypertrophy, this situation reverses to some extent.

In the failing heart, glucose oxidation increases, and β-oxidation falls

Brain

Although the brain represents 2% of total body weight, it obtains 15% of the

cardiac output, uses 20% of total O2, and consumes 25% of the total glucose.
Therefore, glucose is the primary fuel for the brain.

• Blood glucose levels are tightly regulated to maintain the concentration

levels that enable sufficient glucose uptake into the brain via GLUT 1 and

GLUT 3 transporters.

•Because glycogen levels in the brain are minor, normal function depends

upon continuous glucose supply from the bloodstream

Preferred Fuels in the Well-Fed and Fasting States

Question: A woman with a normal weight for her height was

advised that her lipid profile showed an elevation of blood
triglycerides.

The doctor advises Lower fat consumption which

disappoints her since she avidly consumes whole milk.

Consults( tư vấn) a nutritionist, who states that whole milk is

3.5% fat, which corresponds to approximately 11 g of fat in
an 8 ounce serving. If she switches to drinking skim milk
(nonfat), approximately how many additional grams of
carbohydrates should she consume ?
A. 5 grams
8 ounce=11gKcal= 11x9=99(1 Fat=9
Kcal) B. 11 grams
C. 15 grams But 1g Cacbonhydrat= 4 Kcal
D. 25 grams  99x1/4= about 25 Kcal
E. 35 grams
Nhận xét: luôn đổi ra Kcal trước khi tính
gram
 Very small amount of the
carbohydrates Ingested are
monosaccharides

Most of the carbohydrates in foods are in

complex forms

1. Starch (amylose and amylopectin)

2. Sucrose
3. Lactose
 Digest

In the mouth, secreted salivary amylase

randomly hydrolyzes the starch polymers
to dextrins (<8–10 glucoses)

Food into the stomach, the acid pH destroys the salivary amylase

Normal blood glucose concentration is 4–6 mM (72–110 mg/dL)

 Peak=45 min after meal

 Come back down

Normal=90 min

after meal

Independent Insuline:

1. Cataracts( thủy tinh

thể)

2. Renal vascular

3. Hemoglobin
 Involve pathology
GLUCOSE TRANSPORT Insuline binds to receptor
 Dimerize activated
 Cytoplasmic side of receptor: tyrosine kinase
 Increase Vmax= increase uptake, Km not
change
GLUT

Hight Km

proInsuline
radf

 Transfused blood has lower than the expected 2,3-BPG levels, making it

less efficient at delivering oxygen to peripheral tissues

Important enzymes in glycolysis include
Km lowAffinity
hight
Km hightAffinity
low

Glucose Sensing in β-Islet Cells

GLUT 2 and Glucokinase have high Km values for glucose
Glucose First-order kinetics (directly proportional to glucose concentration in
the bloodstream)
Some mutations in the glucokinase gene alter the Km for glucose.
 Decrease the Km (increasing the affinity for glucose) result in
hyperinsulinemia and hypoglycemia.
 Mutations which increase the Km (decreasing the affinity for glucose)
Maturity-onset diabetes of the young (MODY: Đái tháo đường khởi phát ở tuổi
trưởng thành)

Galactosemia:galactose+ blood, accumulation of galactose

in blood

Diabetic: Glc Sornitol( glucitol) Cataracts

 Lactose intolerance

Bl
FRUCTOSE METABOLISM

Aldol

ase B

deficient: fructose accumulate in the cell( Liver, Kidney) toxic

Fructosekinase deficient: fructose not accumulate in the cell, return the blood
PYRUVATE DEHYDROGENASE

Long-term alcoholics Deficient in alcoholics Pyruvate dehydrogenase

unactive increase accumulate Pyruvate Lactac dehydrogenase active
lactic acidosis

 Administrate Glc + Long-term Alcoholics = die

 Need IV thiamine prior

Cofactors and coenzymes used by pyruvate dehydrogenase include:

• Thiamine pyrophosphate (TPP) from the vitamin thiamine
• Lipoic acid
• Coenzyme A (CoA) from pantothenate
• FAD(H2) from riboflavin
• NAD(H) from niacin (some may be synthesized from tryptophan)
 Barbiturates + Complex I =
inhibit complex I( Major)

 Only Minor ATP

created
Barbiturates: Insecticide,
fish poison

Treatment: Met-Hb + CN
 Inhibit CN + Complex IV

 ADP go into F1 create ATP: Controls rate( respiratory rate)

 1ATP=8-8.5 Kcal
 100% energy make= 50% used for make ATP + 50% temperature
Body
 Fever=100% energy for temperature
 H+ back in matrix= increase energy( create ATP + Temperature
body)
 G6P help the glucose from liver to blood maintain
the lever glucose( not in muscle)

Glycogen Storage Diseases

GLUCONEOGENESIS
 -
3P-

Inositol: IP3 Vasopressin, Epinephrin

Cholesterol Digestion

Triglycerides and cholesterol are transported in the blood as lipoproteins.

Lipoproteins are named according to their density, which increases with the percentage of

protein in the particle.

From least dense to most dense:

Bile acids inhibit 7 alpha hydroxylase cholestyramine
bind bile acids remove inhibit 7 alpha hydroxylase
active and increase Bile acids synthesis
Urea form from two source

 Glutamin( Intestine)

 Glutamate( Liver)