2007 First Aid Ch 02 Biochem

PKU.

NADH increase prevents
gluconeogenesis by shunting
pyruvate and oxaloacetate to
lactate and malate.

Kwashiorkor.

low Vitamin B3 (pellagra).

Alkaptonuria.

Familial hypercholesterolemia;

McArdle’s disease.

Locus heterogeneity.

A, D, E, and K.

Vitamin A—Vision
Vitamin D—Bone calcification
—Ca2+ homeostasis
Vitamin K—Clotting factors
Vitamin E—Antioxidant

B1 (thiamine: TPP)
B2 (riboflavin: FAD, FMN)
B3 (niacin: NAD+)
B5 (pantothenate: CoA)
B6 (pyridoxine: PP)
B12 (cobalamin)
C (ascorbic acid)
Biotin
Folate

B12 and folate

dermatitis,
glossitis, and diarrhea.

retinol

Night blindness, dry skin. increased suceptability to measles

Constituent of visual pigments (retinal).

Arthralgias, fatigue, headaches, skin changes, sore throat, alopecia.

Vitamin A

Found in leafy vegetables.

Retinol is vitamin A, so think
Retin-A (used topically for
wrinkles and acne).

thiamine

Vitamin B

Beriberi and Wernicke-Korsakoff syndrome. Seen in alcoholism and malnutrition.
Spell beriberi as Ber1Ber1.

In thiamine pyrophosphate, a cofactor for oxidative
decarboxylation of α-keto acids (pyruvate,
α-ketoglutarate) and a cofactor for transketolase in the HMP shunt.

Dry beriberi––polyneuritis,
muscle wasting.
Wet beriberi––high-output
cardiac failure (dilated
cardiomyopathy), edema.

riboflavin

Vitamin B2

The 2C’s.

Angular stomatitis, Cheilosis, Corneal vascularization.

Cofactor in oxidation and reduction (e.g., FADH2).

"FAD and FMN are derived from
riboFlavin (B2 = 2 ATP)"

niacin

Vitamin B3

Pellagra can be caused by Hartnup disease (↓ tryptophan absorption), malignant carcinoid syndrome (↑ tryptophanmetabolism), and INH (↓ vitamin B6).

Pellagra’s symptoms are the 3 D’s: Diarrhea, Dermatitis,
Dementia (also beefy
glossitis).

Constituent of NAD+, NADP+ (used in redoxreactions). Derived from tryptophan using vitamin B6.

NAD derived from Niacin
(B3 = 3 ATP).

Pellagra

the 3 D’s: Diarrhea, Dermatitis,
Dementia (also beefy
glossitis).

Vitamin B5

pantothenate

Dermatitis, enteritis, alopecia, adrenal insufficiency.

Constituent of CoA (a cofactor for acyl transfers)
and component of fatty acid synthase.

Pantothen-A is in Co-A.

Vitamin B6

pyridoxine

Convulsions, hyperirritability (deficiency inducible by INH and oral contraceptives),
peripheral neuropathy.

Converted to pyridoxal phosphate, a cofactor used in transamination (e.g., ALT and AST),
decarboxylation, and heme synthesis.

cobalamin

Vitamin B12

Macrocytic, megaloblastic anemia; neurologic
symptoms (optic neuropathy, subacute combined
degeneration, paresthesia); glossitis.

Cofactor for homocysteine methylation
(transfers CH3 groups as methylcobalamin)
and methylmalonyl-CoA handling.

Found only in animal products.

Stored primarily in the liver.
Very large reserve pool (several years).

Vitamin B12 deficiency is
usually caused by
malabsorption (sprue,
enteritis, Diphyllobothrium
latum), lack of intrinsic factor (pernicious anemia), or absence of terminal ileum
(Crohn’s disease).

Use Schilling test to detect
deficiency.

Synthesized only by microorganisms.

the patient is given radiolabeled vitamin B12 to drink A normal result shows at least 5% of the radiolabelled vitamin B12 in the urine over the first 24 hours.

Macrocytic, megaloblastic anemia (often no neurologic symptoms, as opposed to vitamin B12 deficiency).

Coenzyme (tetrahydrofolate) for 1-carbon
transfer; involved in methylation reactions.
Important for the synthesis of nitrogenous bases
in DNA and RNA.

FOLate from FOLiage.

PABA is the folic acid
precursor in bacteria. Sulfa
drugs and dapsone
(antimicrobials) are PABA
analogs.

PABA

Folic acid

Dermatitis, enteritis. Caused by antibiotic use,
ingestion of raw eggs.

“AVIDin in egg whites
AVIDly binds biotin.”

Cofactor for carboxylations:
1. Pyruvate → oxaloacetate
2. Acetyl-CoA → malonyl-CoA
3. Proprionyl-CoA → methylmalonyl-CoA

Scurvy––swollen gums, bruising, anemia, poor wound healing.

Necessary for hydroxylation of proline and lysine in
collagen synthesis.
Facilitates iron absorption by keeping iron in Fe+2
reduced state (more absorbable)
Necessary as a cofactor for dopamine →NE.

Vitamin C Cross-links
Collagen. Necessary for hydroxylation of proline and lysine in collagen synthesis.

D2 = ergocalciferol, consumed in milk.
D3 = cholecalciferol, formed in sun-exposed skin.
25-OH D3 = storage form.
1,25 (OH)2 D3 = active form.

Rickets in children (bending bones), osteomalacia
in adults (soft bones), and hypocalcemic tetany.

↑ intestinal absorption of calcium and phosphate.

Hypercalcemia, loss of appetite, stupor. Seen in
sarcoidosis, a disease where the epithelioid
macrophages convert vitamin D into its active form.

Increased fragility of erythrocytes, neurodysfunction.

Vitamin E is for Erythrocytes.

Antioxidant (protects erythrocytes from hemolysis).

Vitamin E is for Erythrocytes.

Neonatal hemorrhage with ↑ PT and ↑ aPTT but normal bleeding time,

Catalyzes γ-carboxylation of glutamic acid residues
on various proteins concerned with blood clotting.

because neonates have sterile intestines and are unable to synthesize
vitamin K.

Synthesized by intestinal flora. Therefore, vitamin
K deficiency can occur after the prolonged use of
broad-spectrum antibiotics.

II, VII, IX, X,

Delayed wound healing, hypogonadism, ↓ adult hair (axillary, facial, pubic); may
predispose to alcoholic cirrhosis.

Zinc

deficiency

Vitamin A (retinol)
Deficiency

Vitamin B1 (thiamine)
Deficiency

gut (ileum) and pancreas.

Vitamin B2 (riboflavin)

Deficiency

Vitamin B5 (pantothenate)

Deficiency

Vitamin B6 (pyridoxine)

Deficiency

Vitamin B12 (cobalamin)

Deficiency

Folic acid

Deficiency

Biotin

Deficiency

Vitamin E
Deficiency

NAD+ is the limiting reagent.

inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to hangover symptoms).

Antabuse

Disulfiram

Ethanol metabolism ↑ NADH/NAD+ ratio in liver, causing diversion of pyruvate to lactate and OAA to malate, thereby inhibiting gluconeogenesis

↑ NADH/NAD+ ratio in liver with shunting away from glycolysis and toward fatty acid synthesis

Kwashiorkor results from a
protein-deficient MEAL:
Malabsorption
Edema
Anemia
Liver (fatty)

protein malnutrition resulting in skin
lesions, edema, liver malfunction (fatty change).
Clinical picture is small child with swollen belly.

Kwashiorkor

energy malnutrition resulting in
tissue and muscle wasting, loss of subcutaneous
fat, and variable edema.

Marasmus

(−) charged DNA loops twice around nucleosome
core (2 each of the (+) charged H2A, H2B, H3,
and H4) to form nucleosome bead.H1 ties nucleosomes together in a string (30-nm
fiber).

H1 is

the only histone that is not
in the nucleosome core.

Condensed, transcriptionally inactive Chromatin

Heterochromatin

Euchromatin

Less condensed, transcriptionally active Chromatin

Purines (A, G) have 2 rings. Pyrimidines (C, T, U)
have 1 ring.

cytosine

uracil.

Glycine
Aspartate
Glutamine

Thymine

Guanine

-Purines (A, G) PURe As Gold: PURines.

-Pyrimidines (C, T, U) CUT the PY (pie): PYrimidines.

3′-5′ phosphodiester bond.

base + ribose + phosphate

Transition-Substituting purine for purine or pyrimidine for
pyrimidine. ( TransItion = Identical type.)

Transversion Substituting purine for pyrimidine or visa versa. (TransVersion = conVersion between types).

Each codon specifies only one amino acid.

no exceptions

More than one codon may code for the same
amino acid.

Methionine encoded by only
one codon.

Read from a fixed starting point as a continuous
sequence of bases.

Some viruses are an exception.

Genetic code is conserved throughout evolution.

Exceptions include
mitochondria, archaebacteria,
Mycoplasma, and some yeasts.

Same aa, often base change in 3rd position of
codon (tRNA wobble).

Silent

Changed aa (conservative––new aa is similar
in chemical structure).

Missense

Change resulting in early stop codon.

Nonsense

Change resulting in misreading of all nucleotides
downstream, usually resulting in a truncated
protein.

Frame shift

Severity of damage: nonsense
> missense > silent.

Eukaryotic genome

Replication begins at a consensus sequence of
AT-rich base pairs.

Prokaryotes

DNA
topoisomerases

Create a nick in the helix to
relieve supercoils.

Primase

Makes an RNA primer on which DNA
polymerase III can initiate replication.

DNA polymerase
III

Elongates the chain by adding
deoxynucleotides to the 3′ end until it reaches
primer of preceding fragment. 3′→ 5′
exonuclease activity “proofreads” each added
nucleotide.

DNA polymerase I

Degrades RNA primer and fills in the gap
with DNA.

DNA ligase

Seals.

DNA polymerase III

DNA polymerase I

Specific endonucleases release the oligonucleotide-
containing damaged bases; DNA polymerase and
ligase fill and reseal the gap, respectively.

Nucleotide excision
repair

Specific glycosylases recognize and remove damaged
bases, AP endonuclease cuts DNA at apyrimidinic
site, empty sugar is removed, and the gap is filled
and resealed.

Base excision repair

Mutated in xeroderma
pigmentosa (dry skin with
melanoma and other cancers).

Nucleotide excision
repair

Specific glycosylases recognize and remove damaged
bases, AP endonuclease cuts DNA at apyrimidinic
site, empty sugar is removed, and the gap is filled

Base excision repair

Unmethylated, newly synthesized string is recognized, M
mismatched nucleotides are remove, and the gap is
filled and resealed.

Mismatch repair

Mismatch repair

Brings together two ends of DNA fragments. No requirement for homology.

Nonhomologous
end joining

DNA and RNA are both synthesized 5′→ 3′.
Remember that the 5′ of the incoming nucleotide
bears the triphosphate (energy source for bond).
The 3′ hydroxyl of the nascent chain is the target.

Protein synthesis also proceeds
in the 5′ to 3′ direction.
Amino acids are linked
N to C.

Massive, Rampant, Tiny.

mRNA is the largest type of RNA.
rRNA is the most abundant type of RNA.
tRNA is the smallest type of RNA.

RNA polymerase I makes rRNA.
RNA polymerase II makes mRNA.
RNA polymerase III makes tRNA.

RNA polymerase (multisubunit complex) makes
all 3 kinds of RNA.

found in death cap mushrooms.

inhibits RNA polymerase II.

α-amanitin

No proofreading function, but can initiate chains.

RNA polymerase II opens DNA at promoter site

AUG (or rarely GUG).

AUG inAUGurates protein
synthesis.

UGA = U Go Away.
UAA = U Are Away.
UAG = U Are Gone.

Site where RNA polymerase and multiple other
transcription factors bind to DNA upstream from
gene locus (AT-rich upstream sequence with
TATA and CAAT boxes).

Promoter

Enhancer

Stretch of DNA that alters gene expression by binding
transcription factors. May be located close to, far
from, or even within (in an intron) the gene whose
expression it regulates.

dramatic ↓ in
amount of gene transcribed.

Operator

Site where negative regulators (repressors) bind.

Exons contain the actual genetic information coding for protein.
Introns are intervening noncoding segments of DNA.

➀ Primary transcript combines with snRNPs to form spliceosome.
➁ Lariat-shaped intermediate is generated.
➂ Lariat is released to remove intron precisely and join two exons.

Occurs in nucleus. After transcription:

1. Capping on 5′ end (7-methyl-G)
2. Polyadenylation on 3′ end (≈ 200 A’s)
3. Splicing out of introns

Initial transcript is called heterogeneous nuclear
RNA (hnRNA).
Capped and tailed transcript is called mRNA.

processed

Only processed RNA is
transported out of the
nucleus.

75–90 nucleotides, cloverleaf form, anticodon end is opposite 3′ aminoacyl end. All
tRNAshave CCA at 3′ end where aa's are bound

Aminoacyl-tRNA synthetase (1 per aa, uses ATP)

in TRNA charging. once aa is on there it will put on a wrong aa

Initiation factors (IFs) help assemble the 30S
ribosomal subunit with the initiator tRNA, are
released when the mRNA and the ribosomal
subunit assemble with the complex.

1. Aminoacyl tRNA binds to A site.
2. Peptidyltransferase catalyzes peptide bond
formation, transfers growing polypeptide to ami
acid in A site.
3. Ribosome advances three nucleotides toward 3′
end of RNA, moving peptidyl RNA to P site.

A site = incoming Aminoacyl
tRNA.

P site = accommodates growing
Peptide.

E site = holds Empty tRNA as
it Exits.

ATP—tRNA Activation
(charging).
GTP—tRNA Gripping and
Going places (translocation).

Removal of N- or C-terminal pro-peptides from zymogens to generate mature proteins.

Phosphorylation, glycosylation, and hydroxylation.

Attachment of ubiquitin to defective proteins to tag them for breakdown.

Mitosis

Remain in G0, regenerate from stem cells.

Never go to G0, divide rapidly with a short G1.

Enter G1 from G0 when stimulated.

Hepatocytes, lymphocytes.

Never go to G0, divide rapidly with a short G1.

Bone marrow, gut epithelium,
skin, hair follicles.

cyclins, cdks, and
tumor suppressors.

synthesis of secretory (exported)
proteins and of N-linked oligosaccharide addition
to many proteins.

RER

RER.

Mucus-secreting goblet cells of
the small intestine and
antibody-secreting plasma
cells

steroid synthesis and detoxification
of drugs and poisons.

SER

Liver hepatocytes and
steroid hormone–producing
cells of the adrenal cortex

SER.

1. Distribution center of proteins and lipids from
ER to the plasma membrane, lysosomes, and
secretory vesicles
2. Modifies N-oligosaccharides
3. Adds O-oligosaccharides
4. Addition of mannose-6-phosphate
5. Proteoglycan assembly
6. Sulfation

failure of addition of mannose-6-phosphate to
lysosome proteins, enzymes
are secreted outside the cell
instead of being targeted to
the lysosome.

I-cell disease:

Characterized by coarse facial
features, clouded corneas,
restricted joint movement,
and high plasma levels of
lysosomal enzymes. Often
fatal in childhood.

I-cell disease

clinical findings

Retrograde,
Golgi → ER.

COP I

Anterograde,
RER → cis-Golgi.

COP II

trans-Golgi →
lysosomes, plasma
membrane → endosomes
(receptor-mediated
endocytosis).

Clathrin

Cylindrical structure 24 nm in diameter and of variable
length. A helical array of polymerized dimers of α-
and β-tubulin (13 per circumference). Each dimer
has 2 GTP bound.

has 2 GTP bound. Incorporated into flagella, cilia,
mitotic spindles.Microtubules are also involved in slow axoplasmic
transport in neurons.

Grows slowly, collapses quickly.

1. Mebendazole/thiabendazole
(antihelminthic)
2. Taxol (anti–breast cancer)
3. Griseofulvin (antifungal)
4. Vincristine/vinblastine
(anti-cancer)
5. Colchicine (anti-gout)

Chédiak-Higashi syndrome

is due to a microtubule
polymerization defect
resulting in ↓ phagocytosis.

9 + + 2 arrangement of microtubules.
Dynein is an ATPase that links peripheral
9 doublets and causes bending of cilium by
differential sliding of doublets.

Cilia structure

Molecular motors
Dynein = retrograde.
Kinesin = anterograde.

Molecular motors
Dynein = retrograde.
Kinesin = anterograde.

Immotile cilia due to a dynein arm defect. Results in male and female infertility (sperm
immotile), bronchiectasis, and recurrent sinusitis (bacteria and particles not
pushed out); associated with situs inversus.

Asymmetric fluid bilayer.
Contains cholesterol (~50%), phospholipids (~50%), sphingolipids, glycolipids,
and proteins.

High cholesterol or long saturated fatty acid content → increased melting temperature.

lecithin

Phosphatidylcholine

Major component of RBC membranes, of myelin, bile, and surfactant (DPPC–
dipalmitoyl PC).
Used in esterification of cholesterol (LCAT is lecithin-cholesterol acyltransferase).

Phosphatidylcholine
(lecithin)

Na+-K+ATPase is located in the plasma membrane
with ATP site on cytoplasmic side. For each ATP
consumed, 3 Na+ go out and 2 K+ come in.

inhibits Na+-K+ATPase by binding to K+ site.

Ouabain

Cardiac glycosides (digoxin,
digitoxin) also inhibit the
Na+-K+ATPase, causing ↑
cardiac contractility.
2K+

Collagen

Most abundant protein in the human body.

Organizes and strengthens extracellular matrix.

Collagen

(90%)––Bone, Skin, Tendon, dentin, fascia, cornea, late wound repair.

Type I

Cartilage (including hyaline), vitreous body, nucleus pulposus.

Type II: carTWOlage.

Type II

Type II: carTWOlage.

skin, blood vessels, uterus,
fetal tissue, granulation tissue.

Type III (Reticulin)

Basement membrane or basal lamina.

Type IV: Under the floor
(basement membrane)..

Type IV

Type IV: Under the floor
(basement membrane).

Reticulin

Type III Collagen

1. Synthesis (RER)
2. Hydroxylation
(ER)
3. Glycosylation
(Golgi)
4. Exocytosis

5. Proteolytic
processing
6. Cross-linking

Translation of collagen α chains (preprocollagen)—
usually Gly-X-Y polypeptide (X and Y are
proline, hydroxyproline, or hydroxylysine).

1. Synthesis (RER)

2. Hydroxylation
(ER)

Hydroxylation of specific proline and lysine
residues (requires vitamin C).

Glycosylation
(Golgi)

Glycosylation of pro-α-chain lysine residues and
formation of procollagen (triple helix of three
collagen α chains).

4. Exocytosis

Exocytosis of procollagen into extracellular
space.

Cleavage of terminal regions of procollagen
transforms it into insoluble tropocollagen.

5. Proteolytic
processing

Reinforcement of many staggered tropocollagen
molecules by covalent lysine-hydroxylysine cross-linkage (by lysyl oxidase) to make col-
lagen fibrils.

6. Cross-linking

Faulty collagen synthesis (Type III is most frequently
affected (resulting in blood
vessel instability) causing:
1. Hyperextensible skin
2. Tendency to bleed (easy bruising)
3. Hypermobile joints
4.Associated with berry aneurysms.

1. Multiple fractures
2. Blue sclerae
3. Hearing loss (abnormal middle ear bones)
4. Dental imperfections due to lack of dentition

Type II is fatal in utero or in
the neonatal period.

Vimentin - Connective tissue

Desmin - Muscle

Cytokeratin - Epithelial cells

Glial fibrillary acid proteins (GFAP) - Neuroglia

Neurofilaments - Neurons

Elastin

Stretchy protein within lungs, large arteries, elastic
ligaments.

Rich in proline and lysine, nonhydroxylated forms.

Emphysema can be caused by
excess elastase activity.

α1-antitrypsin

elastase.

fibrillin.

Fatty acid oxidation (β-oxidation), acetyl-CoA production, Krebs cycle.

Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis
(SER).

heme synthesis, urea cycle, Gluconeogenesis,

"HUGs take 2"

38 ATP

36

malate shuttle

G3P shuttle.

only 2 net ATP

Phosphoryl

(ATP).

(NADH, NADPH, FADH2).

Electrons

(coenzyme A, lipoamide).

Acyl

Acyl

biotin

CO2

(tetrahydrofolates).

1-carbon units

(SAM).

CH3 groups

Aldehydes

(TPP).

Aspartate transcarbamylase (ATCase)

De novo pyrimidine
synthesis

Glutamine-PRPP amidotransferase

De novo purine
svnthesis

PFK-1

Glycolysis

Gluconeogenesis

F 1,6-bisphosphotase (FBP-1)

lsocitrate dehydrogenase

TCA cycle

Glycogen synthase

Glycogen synthesis

Glycogen phosphorylase

Glycogenolysis

Glucose-6-phosphate dehydrogenase (G6PD)

HMP shunt

Acetyl-CoA carboxylase (ACC)

Fatty acid synthesis

Carnitine a~~ltransferase I

Fatty acid oxidation

HMG-CoA synthase

Ketogenesis

Cholesterol synthesis

HMG-CoA reductase

ALA synthase

Heme synthesis

Urea cycle

Carbamoyl phosphate synthase I

S-adenosyl-
methionine (SAM)

SAM the methyl donor man.

SAM transfers methyl units. Regeneration of methionine (and thus SAM) is
dependent on vitamin B12.

Nicotinamides (NAD+, NADP+) and flavin
nucleotides (FAD+).

the HMP shunt.

catabolic processes to
carry reducing equivalents away as NADH.

anabolic processes (steroid
and fatty acid synthesis) as a supply of reducing
equivalents.

1. Anabolic processes
2. Respiratory burst
3. P-450

NADPH

(ubiquitous)
High affinity,
low capacity.
Feedback inhibited by glucose-6- phosphate.

(liver)
Low affinity,
high capacity.
No feedback inhibition.

Phosphorylates excess glucose
(e.g., after a meal) to sequester
it in the liver.

Glucokinase

F2,6BP

(overrides inhibition by ATP
and citrate).

Pyruvate kinase (95%), glucose phosphate (4%),

Associated with hemolytic anemia.

RBCs metabolize glucose
anaerobically (no
mitochondria) and thus
depend solely on glycolysis.

1. Pyrophosphate (B1, thiamine; TPP)
2. FAD (B2, riboflavin)
3. NAD (B3, niacin)
4. CoA (B5, pantothenate)
5. Lipoic acid

α-ketoglutarate
dehydrogenase complex
(same cofactors, similar
substrate and action).

Pyruvate dehydrogenase complex
(same cofactors, similar
substrate and action).

Arsenic inhibits lipoic acid (Pyruvate dehydrogenase complex cofactor):

Vomiting, Rice water stools
Garlic breath

Arsenic

Reaction: pyruvate + NAD+ + CoA → acetyl-CoA + CO2 + NADH.

Activated by exercise:
↑ NAD+/NADH ratio
↑ ADP
↑ Ca2+

Lysine and Leucine––

Causes backup of substrate (pyruvate and alanine),
resulting in lactic acidosis. Can be congenital or
acquired (as in alcoholics due to B1 deficiency).

neurologic defects.

↑ intake of ketogenic nutrients (e.g., high fat content or ↑ lysine and leucine).

6 ATP equivalents

carries amino groups
to the liver from muscle.

can replenish
TCA cycle or be used in
gluconeogenesis.

Transfers excess reducing
equivalents from RBCs and
muscle to liver, allowing
muscle to function
anaerobically (net 2 ATP).
Shifts metabolic burden to the
liver.

Cori cycle

Produces 3 NADH, 1 FADH2,
2 CO2, 1 GTP per acetyl-
CoA = 12 ATP/acetyl-CoA
(2× everything per glucose)

α-ketoglutarate dehydrogenase
complex requires same
cofactors as the pyruvate
dehydrogenase complex (B1,
B2, B3, B5, lipoic acid).

Can IKeep Selling Sex
For Money, Officer?

Citrate
Isocitrate
α-ketoglutarate
Succinyl-CoA
Succinate
Fumarate
Malate
Oxalo-acetate

1 NADH → 3 ATP;

1 FADH2 → 2 ATP.

Uncoupling agents

(UCP, 2,4-DNP, aspirin)

Uncoupling agents

↑ permeability of membrane, causing a ↓ proton
gradient and ↑ O2 consumption. ATP synthesis stops, but electron transport continues.

Electron transport
inhibitors

Electron transport
inhibitors
-Rotenone,
-cyanide,
-antimycin A,
-CO

ATPase inhibitors

Oligomycin

ATPase inhibitors

Directly inhibit mitochondrial ATPase, causing
an ↑ proton gradient, but no ATP is produced
because electron transport stops.

In mitochondria.
Pyruvate → oxaloacetate.

Requires biotin, ATP.
Activated by acetyl-CoA.

Pyruvate carboxylase

In cytosol.
Oxaloacetate → phosphoenolpyruvate.

Requires GTP.

PEP carboxykinase

In cytosol.

Fructose-1,6-bisphosphate →
fructose-6-P.

Fructose-1,6-
bisphosphatase

In ER. Glucose-6-P → glucose.

Pathway Produces Fresh Glucose.

-Pyruvate carboxylase
-PEP carboxykinase
-Fructose-1,6-bisphosphatase
-Glucose-6- phosphatase

Glucose-6-
phosphatase

Above enzymes found only in liver, kidney, intestinal epithelium. Muscle cannot
participate in gluconeogenesis.

hypoglycemia.

Produces NADPH, which is required for fatty acid and steroid biosynthesis and for
glutathione reduction inside RBCs. and nucleotide synthesis

All reactions of this pathway occur in the cytoplasm.
Sites: lactating mammary glands, liver, adrenal cortex––all sites of fatty acid or steroid
synthesis.

No ATP is used or produced.

HMP shunt

Pentose phosphate pathway

(irreversible)

Glucose-6-phosphate dehydrogenase

NADPH

(reversible)

Transketolases (require thiamine)

Ribose-5-phosphate (Ribose-5-phosphate (for
nucleotide synthesis), G3P,
F6P (glycolytic intermediates)

G6PD deficiency is more
prevalent among blacks.

Heinz bodies––altered
Hemoglobin precipitates
within RBCs.

hemolytic anemia due to poor
RBC defense against oxidizing agents (fava beans, sulfonamides, primaquine) and antituberculosis drugs.

Glucose-6-phosphate
dehydrogenase
deficiency

deficiency of aldolase B (recessive). fructose-1-phosphate accumulates, causing a ↓ in available phosphate, which results in inhibition of glycogenolysis
and gluconeogenesis.

hypoglycemia, jaundice, cirrhosis, vomiting.

must ↓ intake of both fructose and sucrose (glucose + fructose).

Involves a defect in fructokinase and is a benign, asymptomatic condition.
Symptoms: fructose appears in blood and urine.

Essential fructosuria

Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive. Damage is
caused by accumulation of toxic substances (including galactitol) rather than absence
of an essential compound.

cataracts, hepatosplenomegaly, mental retardation.

exclude galactose and lactose (galactose + glucose) from diet.

Leu, Lys

Ile, Phe, Trp

Met, Thr, Val, Arg, His

PVT. TIM HALL always argues, never tires":
Phe- Val- Thr- Trp- Ile- Met- His- Arg- Lue- Lys

Asp and Glu

Arg, Lys, and His.
Arg is most basic.
His has no charge at body pH.

Can be acquired (e.g., liver disease) or hereditary
(e.g., ornithine transcarbamoylase deficiency).

Excess NH4 depletes α-ketoglutarate, leading to
inhibition of TCA cycle.

arginine.

Ammonia intoxication: tremor,
slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision.

Degrades amino acids into amino groups. Accounts
for 90% of nitrogen in urine.

Ordinarily, Careless Crappers
Are Also Frivolous About
Urination.

Ornithine + Carbamoyl phosphate go to Citruline which combines with Aspartate going to Argininosuccinate releasing fumarate and arginine (which combines with water to release Urea and ornithine) back to top

from first to last

Tyrosine ^(Thyroxine)
to
Dopamine
to
Dopa ^(Melanin)
to
NE
to
Epi

-Niacin ^ (NAD+/NADP+)
or
-Melatonin
or
-Serotonin

Histamine

to Porphyrin to Heme

Urea
or
Nitric oxide
or
Creatine

GABA (glutamate decarboxylase—requires B6)

Phenylalanine

Tryptophan

Histidine

Glycine

Arginine

Glutamate

tyrosine

––phenylacetate,
phenyllactate, and
phenylpyruvate.

there is ↓ phenylalanine
hydroxylase or ↓ tetrahydrobiopterin cofactor.
Tyrosine becomes essential and phenylalanine builds up, leading to excess phenylketones in urine.

mental retardation, growth retardation, fair skin, eczema, musty body odor.

Treatment: ↓ ↓ phenylalanine (contained in
aspartame, e.g., NutraSweet) and ↑ ↑ tyrosine in diet.

ochronosis

Alkaptonuria

Congenital deficiency of homogentisic acid oxidase in the degradative pathway of
tyrosine. Resulting alkapton bodies cause urine to turn black on standing. Also, the
connective tissue is dark. Benign disease. May have debilitating arthralgias.

Congenital deficiency of either of the following:
1. Tyrosinase (inability to synthesize melanin
from tyrosine)
2. Defective tyrosine transporters (↓ amounts of
tyrosine and thus melanin)

-Can result from a lack of migration of neural
crest cells.

AR - Variable inheritance due to
locus heterogeneity.

Lack of melanin results in an
↑ risk of skin cancer.

1. Cystathionine synthase deficiency (treatment:
↓ Met and ↑ Cys in diet)
2. ↓ affinity of cystathionine synthase for
pyridoxal phosphate (treatment: ↑↑ vitamin
B6 in diet)
3. Methionine synthase deficiency

Results in excess homocysteine
in the urine. Cysteine
becomes essential.

Can cause mental retardation,
osteoporosis, tall stature,
kyphosis, lens subluxation
(downward and inward), and
atherosclerosis (stroke and
MI).

Common (1:7000) inherited defect of renal tubular
amino acid transporter for Cystine, Ornithine,
Lysine, and Arginine in kidneys.

COLA

Excess cystine in urine can lead to the precipitation
of cystine kidney stones.

Treat with acetazolamide to
alkalinize the urine.

Blocked degradation of branched amino acids
(Ile, Val, Leu) "I Love Vermont maple syrup" due to ↓α-ketoacid dehydrogenase.
Causes ↑α-ketoacids in the blood, especially Leu.

Urine smells like maple syrup.

Causes severe CNS defects, mental retardation, and
death.

Purine salvage problem owing to absence of HGPRTase. Results in excess uric acid production.

Findings: retardation, self-mutilation, aggression,
hyperuricemia, gout, and choreoathetosis.

Lesch-Nyhan syndrome

Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase. This prevents DNA synthesis and thus ↓ lymphocyte count.

Adenosine deaminase deficiency

SCID––severe combined
(T and B) immunodeficiency

just VLDL

Glucose
and
Ketone
bodies

In the PHasting state,
PHosphorylate.

BRICK L:
Brain
RBCs
Intestine
Cornea
Kidney
Liver

-GLUT1: RBCs, brain
-GLUT2 (bidirectional): β islet cells, liver, kidney
-GLUT4 (insulin responsive):
adipose tissue, skeletal
muscle

1. ↑ glucose transport
2. ↑ glycogen synthesis and storage
3. ↑ triglyceride synthesis and storage
4. ↑ Na retention (kidneys)
5. ↑ protein synthesis (muscles)

exogenous insulin intake.

insulin

Liver:
⊕Insulin and/or Glucose
-Glucagon and or Epinephrine

Muscle:
⊕Insulin
-Epinephrine

Liver
⊕Epinephrine and or Glucagon
-Insulin

Muscle:
⊕AMP and/or epinephrine
-ATP and/or Insulin

Insulin

"Very Poor Carbohydrate
Metabolism"

Von Gierke’s disease (Type I)

Pompe’s disease(Type II)

Cori’s disease(Type III)

McArdle’s disease (Type V)

12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen within cells.

Severe fasting hypoglycemia, ↑↑ glycogen in liver, ↑ blood
lactate, hepatomegaly.

Glucose-6-phosphate.

-The liver becomes a muscle. (Think about it.)

Cardiomegaly and systemic
findings leading to early death.

Lysosomal α-1,4- glucosidase (acid maltase).

Pompe’s trashes the Pump (heart, liver, and muscle).

Milder form of Type I with normal
blood lactate levels.

Debranching enzyme
α-1,6-glucosidase.

↑glycogen in muscle, but cannot break it down, leading to painful muscle cramps, myoglobinuria with strenuous exercise.

Skeletal muscle glycogen
phosphorylase.

McArdle’s disease

Von Gierke’s disease

Pompe’s disease

Fabry’s disease and Hunter’s syndrome are XR

the rest are AR

Peripheral neuropathy of
hands/feet, angiokeratomas,
cardiovascular/renal disease

α-galactosidase A

Ceramide
trihexoside

Hepatosplenomegaly,
aseptic necrosis of femur,
bone crises, Gaucher’s cells
(macrophages)

β-glucocerebrosidase

Glucocerebroside

"No man picks (Niemann-Pick)
his nose with his sphinger
(sphingomyelinase)."

Progressive neurodegeneration,
hepatosplenomegaly, cherry-
red spot (on macula)

Sphingomyelinase

Sphingomyelin

Progressive neurodegeneration,
developmental delay,
cherry-red spot, lysozymes
with onion skin

' Tay-SaX (Tay-Sachs)
lacks heXosaminidase." Hexosaminidase A

GM2 ganglioside

Peripheral neuropathy,
developmental delay,
optic atrophy

β-galactosidase

Galactocerebroside

Central and peripheral
demyelination with ataxia,
dementia

Arylsulfatase A

Cerebroside sulfate

Developmental delay,
gargoylism, airway obstruction, corneal clouding,
hepatosplenomegaly

α-L-iduronidase

Heparan sulfate,
dermatan sulfate

Mild Hurler’s + aggressive
behavior, no corneal
clouding

Iduronate sulfatase


Heparan sulfate,
dermatan sulfate

Sphingoliposes:
Fabry’s disease - Gaucher’s disease - Niemann-Pick -
Tay-Sachs disease - Krabbe’s disease - Metachromatic
leukodystrophy

Mucopolysaccharidoses:
Hurler’s syndrome -Hunter’s syndrome

Gaucher’s disease

Gaucher’s disease

Niemann-Pick
disease

Tay-Sachs disease

Fabry’s disease

Carnitine deficiency:

In liver: fatty acid and amino acids → HMG-CoA → acetoacetate + β-hydroxybutyrate (to be used in muscle and brain Ketone bodies are metabolized by the brain to 2 molecules of
acetyl-CoA.)

prolonged starvation and diabetic ketoacidosis

Rate-limiting step is catalyzed by HMG-CoA
reductase, which converts HMG-CoA to mevalonate.
2⁄3 of plasma cholesterol is esterified
by lecithin-cholesterol acyltransferase (LCAT).

HMG-
CoA reductase.

statins

Linoeic and linolenic acids.
Arachidonic acid, if linoleic acid is absent.

Eicosanoids are dependent on
essential fatty acids.

Pancreatic lipase

degradation of dietary TG in small intestine.

degradation of TG circulating in chylomicrons and VLDLs.

Lipoprotein lipase

degradation of TG remaining in IDL.

Hepatic TG lipase

degradation of TG stored in adipocytes.

Hormone-sensitive lipase

catalyzes esterification of cholesterol.

Lecithin-cholesterol acyltransferase (LCAT)

mediates transfer of cholesterol esters to other lipoprotein particles.

Cholesterol ester transfer protein (CETP)

Activates LCAT.

A-I

Binds to LDL receptor, mediates VLDL secretion.

B-100

Cofactor for lipoprotein lipase.

C-II

Mediates chylomicron secretion.

B-48

E

Mediates Extra (remnant) uptake.

B-100

E

B-100

C-II
B-100
E

B-48
E

A
B-48
C-II
E

Lipoproteins are composed of varying proportions of cholesterol, triglycerides,
and phospholipids.

LDL and HDL

Delivers dietary triglycerides to peripheral tissues and
dietary cholesterol to liver. Secreted by intestinal
epithelial cells.

Delivers hepatic triglycerides to peripheral tissues
Secreted by liver.

Formed in the degradation of VLDL. Delivers triglycerides and cholesterol to liver, where they
are degraded to LDL.

Delivers hepatic cholesterol to peripheral tissues.
Formed by lipoprotein lipase modification of
VLDL in the peripheral tissue. Taken up by targe
cells via receptor-mediated endocytosis.

Mediates centripetal transport of cholesterol (reverse cholesterol transport, from periphery to liver). Acts as a repository for apoC and apoE (which are
needed for chylomicron and VLDL metabolism).
Secreted from both liver and intestine.

I––hyperchylomicronemia

Chylomicrons

TG, cholesterol

Lipoprotein lipase deficiency
or altered apolipoprotein C-II

IIa––hypercholesterolemia

LDL

Cholesterol

↓ LDL receptors

IV––hypertriglyceridemia

VLDL

TG

Hepatic overproduction of VLDL

microcytic hypochromic anemia.

porphyrias.

Lead poisoning

Acute intermittent porphyria

Porphyria cutanea tarda

Symptoms = 5 P’s:
Painful abdomen, Pink urine,
Polyneuropathy, Psychological
disturbances, Precipitated by drugs

Ferrochelatase and ALA dehydrase

Coproporhyrin and ALA

porphobilinogen deaminase

Porphobilinogen and δ-ALA

Uroporphyrinogen decarboxylase

Uroporphyrin (tea-colored)

Heme is scavenged from RBCs and Fe2+ is reused. Heme →biliverdin →bilirubin

biliverdin

jaundiced newborns are put under UV light which converts bilirubin into urine- solubile products

1. T (taut) form has low affinity for O2.
2. R (relaxed) form has high affinity for O2
(300×).

Hemoglobin exhibits positive
cooperativity and negative allostery (accounts for the sigmoid-shaped O2
dissociation curve for hemoglobin),
unlike myoglobin.

Fetal hemoglobin (2α and 2γ
subunits) has lower affinity
for 2,3-BPG than adult
hemoglobin (HbA) and thus
has higher affinity for O2.

favor T form over R form promoting O2 unloading (negative allosteric regulation).

CO2 (primarily as bicarbonate) binds to amino acids in globin chain at N terminus, but not
to heme.

Administer nitrites in cyanide
poisoning to oxidize hemoglobin to methemoglobin.

Oxidized form of hemoglobin (ferric, Fe3+) that does not bind O2 as readily, but has ↑ affinity for CN–.

in a reduced
state (ferrous, Fe2+).

Form of hemoglobin bound to CO in place of O2.

Carboxyhemoglobin

Methemoglobin

Treat toxic levels of
METHemoglobin with
METHylene blue.

200× greater

1. DNA is denatured by heating to generate 2 separate strands
2. During cooling, excess premade DNA primers anneal to a specific sequence on eac
strand to be amplified
3. Heat-stable DNA polymerase replicates the DNA sequence following each primer

SNoW DRoP:
Southern = DNA
Northern = RNA
Western = Protein

Enzyme-linked immunosorbent assay (ELISA)

to determinewhether a particular
antibody (e.g., anti-HIV) is
present in a patient’s blood
ample. Both the sensitivity

Fluorescent probe binds to specific gene site of interest.
Specific localization of genes and direct visualization of anomalies at molecular level.

Nature and severity of the phenotype varies from 1 individual to another.

Variable expression

Not all individuals with a mutant genotype show the mutant phenotype.

Incomplete penetrance

1 gene has > 1 effect on an individual’s phenotype.

Pleiotropy

Differences in phenotype depend on whether the mutation is of maternal or paternal
origin (e.g., AngelMan’s syndrome [Maternal], Prader-Willi syndrome [Paternal]).

Imprinting

Severity of disease worsens or age of onset of disease is earlier in succeeding generations
(e.g., Huntington’s disease).

Anticipation

If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary
allele must be deleted/mutated before cancer develops. This is not true of oncogenes.

Loss of heterozygosity

Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.

Dominant negative mutation

Tendency for certain alleles at 2 linked loci to occur together more often than
expected by chance. Measured in a population, not in a family, and often varies in
different populations.

Linkage disequilibrium

Occurs when cells in the body have different genetic makeup (e.g., lyonization––
random X inactivation in females).

Mosaicism

Mutations at different loci can produce the same phenotype (e.g., albinism).

Locus heterogeneity

1. no mutation occurring at the locus
2. There is no selection for
any of the genotypes at the locus
3. random mating
4. no migration
being considered

Prader-Willi ( Deletion of normally active paternal allele)

Angelman’s syndrome (Deletion of normally active maternal allele)

Mental retardation, obesity,
hypogonadism, hypotonia.

Mental retardation, seizures,
ataxia, inappropriate laughter
(happy puppet).

Angelman’s syndrome

Prader-Willi

Leber’s hereditary optic
neuropathy;

mitochondrial
myopathies.

Transmitted only through mother. All offspring of
affected females may show signs of disease.

AD

AD

AD

AD

AD

AD

AD

AD

AD

AD

AD

AD

AR

AR

AR

AR

AR

AR

AR

AR
(except Hunter’s),

AR
(except Fabry’s)

AR

AR

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

XR

Be Wise, Fool's GOLD Heeds
False Hope.

Be Wise, Fool's GOLD Heeds
False Hope

Bruton's agammaglobulinemia, Wiskott-Aldrich syndrome, Fragile X, G6PD deficiency, Ocular albinism, Lesch-Nyhan syndrome, Duchenne muscular dystrophy, Hemophilia A and B, Fabry's disease, Hunter's syndrome.

Always bilateral, massive enlargement of kidneys due to multiple large cysts. Patients
present with pain, hematuria, hypertension, progressive renal failure.

are due to mutation in APKD1 (chromosome 16)

Associated with polycystic liver
disease, berry aneurysms, mitral valve prolapsediverticulosis

severe atherosclerotic disease early in life, and tendon xanthomas (classically in the
Achilles tendon); MI may develop before age 20.

Elevated LDL owing to defective or absent LDL receptor. Heterozygotes (1:500) have cholesterol ≈ 300 mg/dL. Homozygotes (very rare) have cholesterol ≈ 700+ mg/dL,

tall with long extremities (arachnodactyly), pectus
excavatum, hyperextensive joints, and long, tapering fingers and toes (see Image
109).

Cardiovascular––cystic medial necrosis of aorta → aortic incompetence and
dissecting aortic aneurysms. Floppy mitral valve.

Ocular––subluxation of lenses.

von Recklinghausen’s disease

Neurofibromatosis type 1

café-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas). Also marked by skeletal disorders (e.g., scoliosis), optic pathway
gliomas, pheochromocytoma, and ↑ tumor susceptibility.

Adult polycystic kidney
disease

Neurofibromatosis
type 1 (von Recklinghausen’s
disease)

pigmented iris hamartomas seen in Neurofibromatosis
type 1

On long arm of chromosome17; 17 letters in von Recklinghausen or Neurofibromatosis

Neurofibromatosis

17 letters in von Recklinghausen or Neurofibromatosis

Bilateral acoustic neuroma, juvenile cataracts

NF2 gene on chromosome 22;
type 2 = 22.

Neurofibromatosis type 2

type 2 = 22

Findings: facial lesions (adenoma sebaceum), hypopigmented “ash leaf spots” on skin,
cortical and retinal hamartomas, seizures, mental retardation, renal cysts, cardiac
rhabdomyomas. Incomplete penetrance, variable presentation.

Tuberous sclerosis

hemangioblastomas of retina/cerebellum/medulla; about half of affected
individuals develop multiple bilateral renal cell carcinomas and other tumors.

Von Hippel–Lindau
disease

Von Hippel–Lindau = 3 words for chromosome 3.

Associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p).
Von Hippel–Lindau = 3 words for chromosome 3.

Findings: depression, progressive dementia, choreiform movements, Symptoms manifest in affected individuals between the ages of 20 and 50.

caudate atrophy and ↓ levels of GABA and ACh in the brain.

Gene located on chromosome 4; triplet repeat disorder. “Hunting 4 food.”

Huntington’s disease

“Hunting 4 food.”

Colon becomes covered with adenomatous polyps after puberty. Progresses to colon
cancer unless resected.

Deletion on chromosome 5; 5 letters in “polyp.”

Familial adenomatous
polyposis

5 letters in “polyp.”

Spheroid erythrocytes; hemolytic anemia; increased MCHC.

Splenectomy is curative.

Autosomal-dominant cell-signaling defect of fibroblast growth factor (FGF) receptor 3.

Results in dwarfism; short limbs, but head and trunk are normal size

Associated with advanced paternal age.

defect in CFTR gene on
chromosome 7, commonly deletion of Phe 508.

Infertility in males due to absent vas deferens.

Cystic fibrosis

Cystic fibrosis

N-acetylcysteine to loosen mucous plugs.

Defective Cl− channel →secretion of abnormally thick mucus that plugs lungs, pancreas, and liver → recurrent pulmonary infections

CFTR channel secretes Cl– in lungs and GI tract and reabsorbs Cl– from sweat.

↑ concentration
of Cl− ions in sweat test is diagnostic.

liver → recurrent pulmonary infections (Pseudomonas species and S. aureus), chronic bronchitis, bronchiectasis, pancreatic
insufficiency (malabsorption [Fat-soluble
vitamin deficiencies (A, D, E,
K] and steatorrhea),
meconium ileus in newborns. Infertility in males due to absent vas deferens. Can present as failure to
thrive in infancy.

Cystic fibrosis

Frame-shift mutation → deletion of dystrophin gene

Frame-shift mutation → deletion of dystrophin gene → accelerated muscle breakdown.

gene → accelerated muscle breakdown. Onset
before 5 years of age. Weakness begins in pelvic
girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle;
cardiac myopathy

Becker’s

Diagnose muscular dystrophies
by ↑ CPK and muscle biopsy.

X-linked defect affecting the methylation and expression of the FMR1 gene. Triplet repeat disorder (CGG)n that may show genetic anticipation (germlike
expansion in females).

Fragile X syndrome

Fragile X syndrome

-mental retardation
-macro-orchidism (enlarged testes)
-long face with a large jaw, -large everted ears,
-autism.

Fragile X syndrome

Huntington’s disease, myotonic dystrophy, Friedreich’s ataxia, fragile X syndrome.

"Try (trinucleotide) hunting
for my fried eggs (X)"

Down syndrome
(trisomy 21),

Edwards’ syndrome
(trisomy 18)

Patau’s syndrome
(trisomy 13)

Down syndrome

Down syndrome

1. mental
retardation,
2. flat facial profile,
3. prominent epicanthal
folds,
4. simian crease,
5. duodenal atresia,
6. congenital heart disease
7. Alzheimer’s disease in affected
individuals > 35 years old,
8. ↑ risk of ALL.

heart disease
(most common malformation is
septum primum–type ASD due to endocardial cushion defects),

↓ levels of α-fetoprotein,
↑β-hCG,

↑ nuchal
translucency.

95% of cases due to meiotic nondisjunction of homologous
chromosomes; associated with advanced maternal age
- 4% of cases due to robertsonian translocation,
- 1% of cases due to Down
mosaicism (no maternal association)

severe mental retardation, rocker bottom feet, low-set ears, micrognathia (small jaw), congenital heart disease, clenched hands,
prominent occiput. Death usually occurs within
1 year of birth.

Edwards’ syndrome

severe mental retardation, microphthalm microcephaly, cleft lip/palate, abnormal forebrain structures, polydactyly, congenital heart disease. Death usually occurs within 1 year of birth.

Patau’s syndrome

Cri-du-chat
syndrome

Congenital deletion of short arm of chromosome 5
(46,XX or XY, 5p−).

microcephaly, severe mental retardation, high-pitched crying/mewing, epicanthal folds,
cardiac abnormalities.

Cri-du-chat syndrome

CATCH-22.

Cleft palate,
Abnormal facies,
Thymic aplasia →
T-cell deficiency, C
ardiac defects,
Hypocalcemia
2° to parathyroid aplasia, microdeletion at
chromosome 22q11. Variable presentation as

DiGeorge syndrome (thymic, parathyroid, and cardiac defects) or velocardiofacial syndrome (palate, facial, and cardiac defects).

3–8 weeks

-pre- and postnatal developmental retardation, -microcephaly,
-facial abnormalities,
-limb dislocation,
-heart and lung fistulas. Mechanism may include

Mechanism may include
inhibition of cell migration.

Fetal alcohol syndrome

The number one cause of congenital malformations in
the United States.

PerIcentric: Involves the centromere, proceeds through meIosis

Paracentric. does NOT Involves the centromere, does NOT proceed through meiosis