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399 Cards in this Set

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condensed, transcriptionally inactive chromatin that is sterically inaccessible
heterochromatin
less condensed, transcriptionally active, sterically accessible chromatin
euchromatin
Why are C-G bonds stronger than A-T bonds?
3 H bonds for C-G

2 H bonds for A-T
Base + ribose =
nucleoside
base+ribose+phospate =
nucleotide
3x pyrimidines
cytosine, uracil, thymine

"CUT the PY"
Purines are made from this precursor
inosine 5' monophosphate (IMP)
Pyrimidines are made from this precursor
orotate
Carbamoyl phosphate is involved in these two metabolic pathways
-de novo pyrimidine synthesis
-urea cycle
Purine synthesis requires these 3x amino acids
glycine, aspartate, glutamine
hydroxyurea inhibits this element of nucleotide synthesis

(FA p.68)
ribonucleotide reductase
6-mercaptopurine inhibits this element of nucleotide synthesis

(FA p.68)
de novo purine synthesis
5-fluorouracil inhibits this element of nucleotide synthesis

(FA p.68)
thymidylate synthase
Methotrexate inhibits this element of nucleotide synthesis

(FA p.68)
dihydrofolate reductase
Trimethoprim inhibits this element of nucleotide synthesis

(FA p.68)
*bacterial* dihydrofolate reductase
Severe combined immunodeficiency (SCID) commonly results from a deficiency of this enzyme
adenosine deaminase
SCID often results from a deficiency of adenosine deaminase. What is the mechanism by which this occurs? (FA 69)
excess ATP --> feedback inhibition of ribonucleotide reductase --> inhibition of DNA synthesis --> decreased lymphocytes
Lesch Nyhan syndrome is a disease of defective purine salvage resulting from deficiency of this enzyme
HGPRT

"He's Got Purine Recovery Trouble"
What property of the genetic code is described below?

Each codon specifies only 1 amino acid
Unambiguous
What property of the genetic code is described below?

More than 1 codon may code for same amino acid
degenerate/redundant
What property of the genetic code is described below?

Code is read from a fixed starting point as a continuous sequence of bases
Non-overlapping ("comma-less")
What property of the genetic code is described below?

Genetic code conserved throughout evolution
Universal
A ____________ DNA mutation results in a base change in the 3rd position of a codon.
Silent mutation - tRNA "wobble" means that same amino acid will be used
What is tRNA wobble?
The base found in the third position of a codon can change without altering the amino acid that the codon represents
Point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid
Missense mutation
A ____________ mutation results in an early stop codon
Nonsense
Discontinuous sequences of DNA found on the lagging strand during DNA replication
Okazaki fragments
sequence in the genome where DNA replication begins
origin of replication
Y shaped region where strands of DNA are being split apart and the leading/lagging strands are synthesized
replication fork
Enzyme that unwinds DNA at replication fork
helicase
Component of DNA replication that prevents separated DNA strands from re-annealing
single-stranded binding proteins
enzyme that creates a nick in the helix to relieve supercoils created during replication
topoisomerases
What is the action of fluoroquinolone abx?
inhibit DNA gyrase (type of topoisomerase)
What is the function of the primase enzyme?
Makes an RNA primer on which DNA Pol III can initiate replication
Prokaryotic enzyme that elongates the leading strand during DNA replication by adding nucleotides to the 3' end
DNA Pol III
Prokaryotic enzyme that degrades RNA primer and fills that space with DNA
...
Function of DNA ligase?
Forms the bond between neighboring Okazaki fragments on the lagging strand during DNA replication
Name the process:

endonucleases remove an oligonucleotide containing damaged bases; DNA Pol and ligase fill/reseal the gap
nucleotide excision repair
Name the process:

During DNA replication, glycosylases recognize and remove damaged bases, empty sugar is removed, gap is filled and resealed
Base excision repair
Name the process:

Unmethylated, newly synthesized DNA strand is proofread, mismatched nucleotides removed, gap is filled and resealed
Mismatch repair
What hereditary condition involves defects in mismatch repair genes?
Hereditary non-polyposis colorectal cancer (HNPCC)
What chemical group is required in the 3' position of a nt for DNA/RNA synthesis to continue?
hydroxyl group
most abundant type of RNA?
rRNA

"Rampant, Massive, Tiny"
longest type of RNA
mRNA

"Rampant, massive, tiny"
Smallest type of RNA
tRNA

"Rampant, massive, tiny"
mRNA start codon
AUG

"AUG inAUGurates protein synthesis
AUG codes for...

___________ in a prokaryote
___________ in a eukaryote
-formyl methionine (f-Met)
-methionine
Site where RNA pol and other txn factors bind DNA upstream from a coding region of a gene
promoter
What is the result of a mutation to a promoter?
dramatic decrease in txn of a protein
Segment of DNA that alters gene txn by binding txn factors that promote gene expression
Enhancer
Site of DNA where negative regulators (repressors) bind
silencer
promoter, enhancer, silencer

Which of the above must be located upstream of a coding region of a gene? Why?
PROMOTER must be upstream because RNA Pol binds there
RNA Pol I produces ___________
rRNA
RNA Pol II produces ___________
mRNA
RNA Pol III produces ___________
tRNA
This compound, found in death cap mushrooms, inhibits RNA Pol II. This causes liver failure if the compound is ingested
alpha-amanitin
Initial DNA transcript is called
heterogenous nucleoar RNA (hnRNA)

no 5' cap, no polyadenylation, still contains introns
What processes are required for a segment of hnRNA to become mRNA (x3)?
-5' capping
-3' polyadenylation
-splicing out of introns
splicing of RNA begins when the primary transcript combines with snRNP's and other proteins to form the ______________
spliceosome
Different exons can be combined by ___________ ______________ to make unique proteins in different tissues
alternative splicing
heritable changes in phenotype or gene expression caused by mechanisms other than alterations to underlying DNA sequence
epigenetic changes
3-nucleotide sequence at the 3' end where the amino acid is attached to the tRNA molecule
CCA-OH

OH = hydroxyl group
enzyme that attaches amino acid to tRNA
aminoacyl tRNA synthetase
two factors in *translation* responsible for accuracy of amino acid-codon genetic code
-aminoacyl tRNA synthetase (specific to each tRNA)
-binding of tRNA to amino-acid specific codon
This antibiotic subclass binds the 30s subunit, preventing attachment of aminoacyl-tRNA
tetracyclines
Eukaryote or prokaryote initiation?

40S+60S --> 80S
Eukaryote

"Even"
Prokaryote or eukaryote?

30S + 50S --> 70S
prOkaryote = "Odd"
Review steps in protein synthesis

(FA p 75)
...
Give the term for the definition:

process by which ribosome advances 3 nts towards 3' end of RNA, moving peptidyl RNA to P site
translocation
this tRNA site on the ribosome receives the incoming aminoacyl tRNA
A-site
this tRNA site on the ribosome holds the tRNA to which the growing peptide is attached
P-site
this tRNA site on the ribosome holds the empty tRNA before it leaves the ribosome
E site
this antibiotic class inhibits formation of the initiation complex (DNA tln) and causes misreading of mRNA
aminoglycosides
this antibiotic inhibits 50S peptidyltransferase in prokaryotes
chloramphenicol
these antibiotic classes (x2) bind to the 50S subunit of the bacterial ribosome, blocking translocation
-macrolides
-clindamycin
defective proteins are tagged with ____________ to target them to the proteasome for destruction
ubiquitin
organelle in which steroid synthesis and detoxification of drugs/poisons occurs
smooth ER
site of synthesis of proteins in the secretory pathways
rough ER
special name for RER in neurons, which synthesizes enzymes and peptide neurotransmitters
Nissl bodies
Two types of cells that are rich in rough ER
secretory cells:

-goblet cells
-plasma cells
Regulatory proteins that control cell cycle events; different types of this protein depending on the stage of the cell cycle
Cyclins
Protein that, when bound to cyclin, phosphorylates downstream targets to move the cell through the cell cycle
CDK = cyclin-dependent kinase
Begin with G0, and give the subsequent four phases of the cell going through the cell cycle.
G1 --> S --> G2 --> M
Three phases of the cell cycle that are part of interphase
G1, S, G2
Rb and p53 block transition between these phases of the cell cycle
G1 --> S
Cell type that remains in G0; no division
permanent
Cell type that enters G1 from G0 only when stimulated
quiescent
Cell type that never goes to G0; remains in cell cycle, divides rapidly and continuously
labile
Distribution center of proteins and lipids from ER to the plasma membrane, lysosomes, and secretory vesicles
Golgi apparatus
Vesicular trafficking protein responsible for retrograde transport, from Golgi --> ER
COP I
Vesicular trafficking protein responsible for anterograde transport, from RER --> cis-Golgi
COP II
Vesicular trafficking protein responsible for moving proteins from [trans-Golgi --> lysosomes/plasma membrane --> endosomes (receptor mediated endocytosis)]
Clathrin
inherited lysosomal storage disorder resulting from failure of addition of *mannose-6-phosphate* to lysosome proteins
I-cell disease
This polysaccharide targets proteins to the lysosome
mannose-6-phosphate
A microtubule is a cylindrical structure composed of a helical array of dimers.

The dimers are made up of these two proteins.
alpha and beta tubulin
These proteins transport cellular cargo towards opposite ends of the microtubule (x2)
dynein
kinesin
molecular motor protein that transports retrograde to the microtubule (+ end towards - end)
dynein
molecular motor protein that transports anterograde to the microtubule (- end towards + end)
kinesin
microtubule polymerization defect that results in decreased phagocytosis
Chediak-Higashi syndrome

(p. 78)
Cilia are composed of a _________ arrangement of microtubules
9 + 2
Kartagener's syndrome results when cilia are immotile due to a defect in this protein
dynein
Kartagener's syndrome results in immotile cilia due to a defect in dynein. What (somewhat predictable) effects should this demonstrate in the afflicted patient?
-impaired hearing
-infertility (sperm immotile)
-recurrent sinusitis
-bronchiectasis
What effect does high cholesterol or long saturated fatty acid content have on the physical properties of a plasma membrane?
increased chol/long chain FA's -->

increased melting temp
decreased fluidity
Type of collagen found in bone, skin, tendon
Type I
Type of collagen found in cartilage, vitreous body, nucleus pulposus
Type II
Type of collagen found in skin, blood vessels, uterus, fetal tissue, granulation tissue
Type III
Type of collagen found in basement membranes and basal laminae
Type IV

"Under the floor" in lungs, kidney, vessels
Two amino acid residues are hydroxylated during collagen synthesis.

Hydroxylation of this residue secures the three collagen chains in a triple helix.
Proline
Two amino acid residues are hydroxylated during collagen synthesis.

Hydroxylation of this residue is required for covalent cross-linking to produce collagen fibrils.
Lysine
Hydroxylation of proline and lysine residues requires this vitamin.
Vit C

(scurvy - vitamin C deficiency)
Collagen chains in the RER, just after synthesis, are known as ___________
pre-pro-collagen
What is the sequence of amino acids in pre-pro-collagen?
Gly-X-Y

X,Y are proline, hydroxyproline, or lysine
Glycosylation of residues in pre-pro-collagen results in formation of triple helix, which is known as _______________
pro-collagen
Procollagen is secreted into the extracellular space, where cleavage of its terminal regions transforms it into __________
tropocollagen
Cross-linking of tropocollagen forms ____________________
collagen fibrils
Inability of individual collagen chains to form the triple helix results in this heritable disease.
Osteogenesis imperfecta

(triple helix can't form)
Failure of collagen fibrils to cross-link once they have reached the ECM results in this heritable disease.
Ehlers-Danlos syndrome.
This type of collagen is most frequently affected in Ehlers-Danlos syndrome
Type III
Three characteristic features of Ehlers-Danlos 2ry to faulty collagen synthesis:
1. hyperextensible skin
2. tendency to bleed (easy bruising)
3. hypermobile joints
Osteogenesis imperfecta results from abnormality in this collagen subtype
Type I

TypeI forms bone, skin, tendon
Characteristic clinical features of osteogenesis imperfecta (x4)
1. multiple fractures with minimal trauma
2. blue sclerae (very thin choroid)
3. hearing loss (abnormal middle ear bones)
4. dental imperfections
Alport's syndrome most frequently results from a defect in this type of collagen
Type IV
Two important clinical features of Alport's syndrome
-progressive hereditary nephritis
-deafness
Marfan's syndrome is caused by a defect in the _________________ protein
fibrillin
"stretchy protein" in the lungs, large arteries, elastic ligaments, vocal cords, and ligamenta flava
elastin
Elastin is composed of ___________ with ____________ scaffolding
-tropoelastin
-fibrillin
Elastin is...

broken down by _____________ (enzyme), which is inhibited by ____________________ (enzyme)
-elastase
-a1 antitrypsin
How can a1-antitrypsin deficiency lead to emphysema?
a1-AT deficiency --> uninhibited elastase activity --> breakdown of elastin --> tissues supporting structure/function of lungs are destroyed (emphysema)
What is the polymerase chain reaction (PCR) used for?
amplify a desired fragment of DNA
Three steps of PCR
(1) denaturation, (2) annealing, (3) elongation

FA p. 81
This laboratory technique is used for the size separation of PCR products (smaller molecules travel further)
Agarose gel electrophoresis
This blotting technique is used to detect DNA samples
Southern blot

"SNoW DRoP"
This blotting technique is used to detect RNA in a sample
Northern blot

"SNoW DRoP"
This blotting technique is used to detect proteins in a sample
Western blot

"SNoW DRoP"
Lab technique in which thousands of nucleic acid sequences are arranged in grids on slides; profiles expression levels of thousands of genes simultaneously
DNA Microarrays
rapid immunologic lab technique for testing antigen-antibody reactivity
ELISA = enzyme linked immunosorbent assay
What indicates a positive result in an ELISA test?
Usually, if the test substance is present, an intense color reaction in the test solution
In this lab technique used for specific localization of genes/direct visualization of anomalies, fluorescent DNA or RNA probes are used to bind to the site of interest
Fluoresence in-situ hybridization (FiSH)
What is "cloning" as a lab technique?
production of recombinant DNA molecule that is self perpetuating
When DNA sequences are cloned in the lab, why are the inserted into bacterial plasmids that contain resistance genes to various antibiotics?
Can select for the presence of the plasmid by transfecting bacteria and growing them on a medium containing the antibiotic
process in which metaphase chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern
karyotyping
Genetic term:

Neither of two alleles is dominant
Codominance
Genetic term:

The nature of and severity of a particular phenotype can vary between individuals
variable expression
Genetic term:

Not all individuals with the mutant genotype show the mutant phenotype
incomplete penetrance
Genetic term:

one gene has >1 effect on an individual's phenotype
Pleiotropy
Genetic term:

Differences in phenotype depend on whether the mutation is of maternal or paternal origin
Imprinting
Genetic term:

Severity of a disease worsens or age of onset is earlier in later generations
anticipation
Genetic term:

If a patient inherits or develops a mutation in a tumor suppressor gene, complementary allele must also be deleted/mutated before cancer can develop
Loss of heterozygosity
Genetic term:

Heterozygote produces a nonfunctional, altered protein that prevents the normal gene product from performing its function
Dominant negative mutation
Genetic term:

Tendency for certain alleles at two linked loci to occur more often together than expected by chance
Linkage disequilibrium
Genetic term:

Cells in the body of the same organism do not all have the same genetic makeup
mosaicism
Genetic term:

Mutations at different loci produce the same phenotype
Locus disequilibrium
Genetic term:

Presence of both normal and mutated mtDNA, resulting in variable expression of mitochondrial inherited disease
Heteroplasmy
Genetic term:

Offspring receives two copies of a chromosome from 1 parent and no copies from other parent
Uniparental disomy
Give the Hardy-Weinberg equilibrium equations for:

(a) Disease prevalence
(b) allele prevalence
(c) heterozygote prevalence
(a) p^2 + 2pq + q^2 = 1
(b) p + q = 1
(c) 2pq
Biological process by which one allele at a particular locus is inactivated by methylation (such that only a single allele is active)
imprinting
Genetic disease resulting from delection of normally active Paternal allele on chromosome 15
Prader-Willi syndrome
Genetic disease resulting from a normally active Maternal allele on chromosome 15
AngelMan's syndrome
Autosomal dominant disorders often are due to defects in _______________ genes
structural
Autosomal recessive disorders often are due to defects in _______________ genes
enzyme

(--> enzyme deficiency or absence)
Mode of inheritance of genetic disorder such that

(a) either male or female offspring of affected mother may be affected
(b) all female offspring of the affected father are diseased
X-linked dominant
X-linked dominant disorders in which increased phosphate wasting at proximal tubule leads to a rickets-like presentation
hypophosphatemic rickets
Mode of inheritance in which the damaged alleles can ONLY be transmitted through the mother. All offspring of affected females may show signs of the disease
mitochondrial inheritance
FA notes that disorders of mitochondrial inheritance have "variable expression in population due to heteroplasmy." What does this mean from a biochemical standpoint?
Heteroplasmy: mixture of mitochondria, some containing normal DNA and some containing mutant DNA --> proportion of normal to mutant DNA influences disease severity
AD genetic disorder:

cell signaling defect in FGF3 --> dwarfism
Achondroplasia
Autosomal dominant:

Bilateral, massive enlargement of kidneys due to large cysts
autosomal dominant polycystic kidney disease
Autosomal dominant:

elevated LDL due to defective or absent LDL receptor
familial hypercholesterolemia
Autosomal dominant:

inherited disorder of blood vessels with telangiectasia, recurrent epistaxis, skin discoloration, & arteriovenous malformation
hereditary hemorrhagic telangiectasias
another name for hereditary hemorrhagic telangiectasia
Osler-Weber-Rendu syndrome
Autosomal dominant:

spheroid erythrocytes due to spectrin or ankyrin defect --> hemolytic anemia
hereditary spherocytosis
Autosomal dominant:

depression, progressive dementia, choreiform movements, atrophy of caudate nucleus, decreased GABA and ACh in the brain
Huntington's disease
What chromosome is the gene for Huntington's located on?
Chromosome 4

"Hunting 4 food"
What trinucleotide repeat occurs in Huntington's?
CAG
Marfan's syndrome involves a mutation of this gene
fibrillin
Autosomal dominant:

connective tissue disorder affecting skeleton, heart, eyes
Marfan's syndrome
AD disease of the connective tissue associated subluxation of the lenses
Marfan's syndrome
Autosomal dominant:

familial tumors of endocrine glands
multiple endocrine neoplasia (MEN)
Autosomal dominant:

cafe au lait spots, neural tumors, Lisch nodules, skeletal disorders, optic pathway gliomas
Neurofibromatosis -1
Autosomal dominant:

bilateral acoustic schwannomas, juvenile cataracts
Neurofibromatosis-2
NF2 gene located on this chromosome
22
NF-1 is also known as _________________
von Recklinghausen's disease
Autosomal dominant:

rare, multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.
tuberous sclerosis
Autosomal dominant:

adenoma sebaceum, "ash leaf spots" on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cysts/renal angiolipomas, cardiac rhabdomyomas, astrocytomas
tuberous sclerosis
Autosomal dominant:

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 disease results 2ry to deletion of VHL gene, which results in constitutive expression of __________, as well as activation of ___________________
-HIF (txn factor)
-angiogenic growth factors

Result is neovascularization, carcinogenesis
Why are males with CF infertile?
Bilateral absence of vas deferens
Most common CF mutation
delta F508
AR defect in CFTR gene leads to an abnormality of the Cl- channel. What pathology does this cause?
Secretion of abnormally thick mucus that plubs lungs, pancreas, liver
Why do individuals with CF have deficiencies in fat soluble vitamins?
Mucus plugs in pancreas --> deficiency of digestive enzymes --> fat malabsorption
What is the normal function of the dystrophin protein?
connects cytoskeleton of muscle fiber to surrounding extracellular matrix
muscular dystrophy is diagnosed with these two techniques?
muscle bx, increased CPK (2ry to muscle breakdown)
What is the difference between Duchenne's and Becker's muscular dystrophy?
Duchenne's - Deleted dystrophin
Becker's - decreased or abnormal dystrophin
Fragile X syndrome involves defect in this gene
FMR-1
Fragile X syndrome results from an expansion of this trinucleotide repeat
CGG
2nd most common cause of genetic mental retardation
Fragile X
most common cause of genetic mental retardation
Down's syndrome
Four TNR expansion diseases
Huntington's, myotonic dystrophy, Friedrich's ataxia, fragile X
What is genetic anticipation?
Disease severity increases and age of onset decreases in successive generations (assoc with TNR disorders)
Down's syndrome is a trisomy of chromosome _______
21

(Drinking age = 21)
Edwards' syndrome is a trisomy of chromosome _______
18

(Election age = 18)
Patau's syndrome is a trisomy of chromosome _______
13

(Puberty = 13)
Autosomal trisomy:

mental retardation, flat facies, prominent epicanthal folds, simian crease, increased risk of ALL + early onset Alzheimer's disease
Down's syndrome = trisomy 21
Most cases (95%) of Down's syndrome are due to ______________; the remainder (4%) are due to ______________.
-meiotic nondisjunction
-Robertsonian translocation
Autosomal trisomy:

micrognathia, severe mental retardation, rocker bottom feet, clenched hands
Edwards syndrome - trisomy 18
Autosomal trisomy:

severe mental retardation, rocker-bottom feet, cleft lip/Palate, holoprosencephaly, polydactyly
Patau's syndrome
Name the 5 acrocentric chromosomes (chromosome whose the p (short) arm is so short that is hard to observe, but still present)
13, 14, 15, 21, 22
Congenital microdelection of the short arm of chromosome 5 leads to this disorder
Cri-du-chat syndrome
Congenital microdelection of the long arm of chromosome 7 leads to this disorder
Williams syndrome
Genetic disorder involving a partial chromosomal deletion that presents with:

mental disability, heart defects, "elfin facies," well-developed verbal skills and extreme friendliness with strangers
Williams syndrome
22q11 delection syndromes cause "CATCH-22" pathology due to aberrant development of these embryonic structures
3rd and 4th branchial pouches
CATCH-22 pathology associated with 22q11 deletion syndromes?
Cleft palate
Abnormal facies
Thymic aplasia --> T cell deficiency
Cardiac defects
Hypocalcemia 2ry to PTG aplasia
22q11 deletion syndrome involving thymic, parathyroid, and cardiac defects
DiGeorge syndrome
22q11 deletion syndrome involving palate, facial, and cardiac defects
velocardialfacial syndrome
Name the four fat soluble vitamins
A, D, E, K
Vitamin B1 aka
thiamine
Vitamin B2 aka
riboflavin
Vitamin B3 aka
niacin
Vitamin B5 aka
pantothenic acid
Vitamin B6 aka
pyridoxine
Vitamin B12 aka
cobalmin
Vitamin C aka
ascorbic acid
Vitamin A aka
retinol
this vitamin is an antioxidant and a constituent of visual pigments; deficiency leads to night blindness and dry skin
vitamin A
this vitamin is required as part of thiamine pyrophosphate (TPP), a cofactor for dehydrogenase enzymes that work on alpha-ketoacids
B1 (thiamine)
B1 deficiency can cause this condition, which presents with confusion, ophthalmoplegia, ataxia+ confabulation, personality change, and permanent memory loss
Wernicke-Korsakoff syndrome
Two states in which B1 deficiency is often seen
-malnutrition
-alcoholism
B1 deficient patients can suffer from this malnutrition syndrome, which has two subtypes
Beri-Beri

Dry: polyneuritis, symmetrical muscle wasting
Wet: high output cardiac failure (DCM), edema
B1 deficiency --> impaired glucose breakdown --> ATP depletion

Which tissues are most severely affected (x2)?
Highly aerobic tissues = heart, brain
FAD and FMN are derived from this vitamin
Vit B2 - cofactor in oxidation/reduction

(riboFlavin --> FAD, FMN)
Inflammation of the lips, scaling/fissures at the corners of the mouth, and corneal vascularization are called _____________ and seen in patients deficient in vitamin ______
-cheilosis
-B2
NAD/NADP are derived from this vitamin
Vit B3 (niacin)

*N*iacin --> Nad/Nadp
Vit B3 (niacin) is derived from this amino acid
tryptophan
synthesis of Vit B3 (niacin) requires this vitamin
B6 (pyridoxine)
Regarding Vit B3 (niacin):

a. mild deficiency --> (?)
b. severe deficiency --> (?)
a. glossitis
b. pellagra (3 D's) = diarrhea, dermatitis, dementia
How can each of the following lead to Vit B3 (niacin) deficiency?

a. Hartnup disease
b. carcinoid syndrome
c. INH therapy
a. dec TRP absorption
b. inc TRP metabolism
c. dec Vit B6
Other than to correct deficiency, why might Vit B3 (niacin) be given therapeutically?
Bridge to GI:

Niacin inhibits lipolysis in adipose tissue --> used as a lipid-lowering agent
What side effect occurs with excess Vit B3 (niacin)?
Facial flushing (occurs with pharmacologic doses for tx of hyperlipidemia)
This vitamin is an essential component of both (1) CoA (cofactor for acyl transfers) and (2) fatty acid synthase
Vit B5 (pantothen*ate*)

Pantothen-*A* is found in Co-A
This vidamin is converted to pyridoxal phosphate, a cofactor in various reactions
Vit B6 (pyridoxine)
Why does a deficiency in vit B6 (pyridoxine) cause convulsions?
B6 --(conversion)--> pyridoxal phosphate

Pyridoxal phosphate required for synthesis of GABA, 5-HT, NE, and EPI synthesis
Deficiency of either of these vitamins leads to macrocytic anemia
Folate, B12
Deficiency in this vitamin leads to megaloblastic anemia and neurologic sx
B12

Subacute combined degeneration - demyelination of dorsal columns, LCST
A patient presents with vit B12 deficiency. Is this likely to be nutritional in nature?
No. A very large reserve pool (several years' worth) is stored in the liver. Deficiency can result from malabsorption (sprue, fish tapeworm), lack of intrinsic factor (pernicious anemia, gastric bypass), or absence of terminal ileum.
A patient presents with folate deficiency. Is this likely to be nutritional in nature?
Yes, only a very small pool of folate exists. Found in green leaves.

Deficiency most pronounced in pregnant women and alcoholics.
A patient has macrocytic anemia. What physical exam finding can be used to differentiate between folate and B12 deficiency?
Neurologic sx = B12
No neurologic sx = folate

Patients with B12 deficiency experience subacute combined degeneration, a demyelinating disease of the dorsal columns and LCST
This test is used to determine etiology of B12 deficiency.
Schilling test
B12 is a cofactor for this enzyme
homocysteine methyltransferase
What compound serves as the "methyl donor man" in the conversion of methionine to homocysteine?
SAM "the methyl donor man"

SAM = S-adenosyl-methionine = ATP + methionine
Folate deficiency in pregnancy can have this adverse consequence
neural tube defects
This vitamin is a cofactor for carboxlation enzymes
Vit B7 (Biotin)
Biotin aka
vit B7
Three functions of vitamin C:

a. facilitates absorption of _________
b. necessary for _______________ during collagen synthesis
c. necessary for the conversion of ________ to _________
a. iron (keeps iron in the Fe2+ state)
b. hydroxylation of proline/lysine residues
c. dopamine to NE
deficiency of vitamin C is called
scurvy

defective collagen synthesis --> impaired wound healing, poor bone formation, fragile capillaries
Why does excessive ingestion of raw eggs lead to biotin (Vit B7) deficiency?
Raw eggs contain AVIDIN, which binds biotin.
Give the alternate names for the compounds below

a. D2 =
b. D3 =
a. D2 = ergocalciferol
b. D3 = cholecalciferol
What is the primary function of Vitamin D?
increased intestinal absorption of calcium and phosphate
Vit D deficiency is called __________ in children, and __________ in adults
RICKETS in children, OSTEOMALACIA in adults
Excess vitamin D can be seen in this systemic disease, 2ry to increased activation of Vit D by epithelioid macrophages
sarcoidosis
This vitamin is an antioxidant, and protects erythrocytes and cell membranes from free radical damage
Vitamin E
What is the hematologic consequence of Vit E deficiency?
hemolytic anemia

Vit E deficiency --> decreased protection of erythrocytes from free radical damage --> inc erythrocyte fragility
This vitamin is a cofactor for gamma carboxylation of glutamic acid residues
Vitamin K
What is the source of vitamin K?
endogenous intestinal flora
Why are neonates susceptible to vitamin K deficiency?
Intestine is sterile --> normal flora required for VitK synthesis
Why are individuals taking antibiotics susceptible to vitamin K deficiency?
ABX --> death of intestinal flora --> decreased vitK production
Vit K is necessary for the synthesis of these clotting factors
II, VII, IX, and X ("1972 = ten, nine, seven, and two")

Proteins C and S
ethanol --(1)--> acetaldehyde --(2)--> acetate

a. What enzyme is responsible for conversion (1)?
b. For conversion (2)?
a. alcohol dehydrogenase
b. acetaldehyde dehydrogenase
ethanol --(1)--> acetaldehyde --(2)--> acetate

reaction (1) takes place where?
reaction (2) takes place where?
(1) cytosol
(2) mitochondria
ethanol --(1)--> acetaldehyde --(2)--> acetate

methanol --(1)--> b. _____________ --(2)--> c. _____________

When a person drinks methanol, what compounds appear (via the same metabolic pathway as ethanol) in blanks b and c?
b. formaldehyde
c. formic acid

Formaldehyde is highly toxic to humans
methanol --(1)--> formaldehyde --(2)--> formate

This medication inhibits alcohol dehydrogenase (1) and is the antidote for methanol/ethylene glycol poisoning
fomepizole
ethanol --(1)--> aldehyde --(2)--> acetate

this medication inhibits acetaldehyde dehydrogenase (2), leading to accumulation of acetaldehyde
disulfuram

*acetaldehyde* is the compound responsible for hangovers -- with disulfuram, it accumulates more quickly, resulting in unpleasant sx (used to treat alcohol addiction)
Limiting reagent in EtOH metabolism
NAD+

ethanol --------------------->acetaldehyde
|
NAD+ ----> NADH
Ethanol metabolism increases NADH/NAD ratio in liver --> causes (1) pyruvate to lactate, (2) OAA to malate

Reactions (1) and (2) convert NADH to NAD.

However, as a consequence, certain processes are altered: __________ is inhibited and ___________ is stimulated.
-gluconeogenesis inhibited
-fatty acid synthesis stimulated
Metabolism of large amounts of ethanol impairs gluconeogenesis and stimulates fatty acid synthesis. What are the pathological consequences of these metabolic changes?
impaired gluconeo --> hypoglycemia

stimulated FA synthesis --> hepatocellular steatosis
Protein malnutrition results in this condition characterized by skin lesions, edema, and liver malfunction.

Presentation: small child with swollen abdomen
kwashiorkor
Total calorie malnutrition results in this condition characterized by tissue and muscle wasting, loss of subcutaneous fat
marasmus
Why do patients with kwashiorkor have a swollen abdomen?
protein deficiency --> liver malfunction --> decreased albumin --> decreased oncotic pressure --> ASCITES
Consider the following metabolic processes: Fatty acid oxidation, acetyl-CoA production, TCA cycle, oxidative phosphorylation

In what location do these take place?
mitochondria
Consider the following metabolic processes: Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis, steroid synthesis.

In what location do these take place?
Cytoplasm
Which 3x metabolic processes have steps occurring in both the mitochondria and the cytoplasm?
heme synthesis, urea cycle, gluconeogenesis

"HUGs take two"
This enzyme class adds high-energy phosphates to substrates
kinase
This enzyme class adds inorganic phosphate onto a substrate without using ATP
phosphorylase
enzyme that removes a phosphate group from a substrate
phosphatase
enzyme that *oxidizes* a substrate
dehydrogenase
enzyme that adds 1 carbon with biotin as a cofactor
carboxylase
Rate determining enzyme for glycolysis
phosphofructokinase-1
Rate determining enzyme for gluconeogenesis
fructose-1,6-bisphosphatase
Rate determining enzyme for TCA cycle
isocitrate dehydrogenase

[isocitrate --> a-ketoglutarate]
Rate determining enzyme for glycogen synthesis
glycogen synthase
Rate determining enzyme for glycogenolysis
glycogen phosphorylase
Rate determining enzyme for HMP shunt
glucose-6-phosphate dehydrogenase
Rate determining enzyme for [de novo pyrimidine synthesis]
Carbamoyl phosphate synthetase II
Rate determining enzyme for de novo purine synthesis
Glutamine PRPP amidotransferase
Rate determining enzyme for urea cycle
Carbamoyl phosphate synthetase I
Rate determining enzyme for fatty acid synthesis
Acetyl CoA carboxylase (ACC)
Rate determining enzyme for fatty acid oxidation
Carnitine acyltransferase I
Rate determining enzyme for ketogenesis
HMG-CoA synthase
Rate determining enzyme for cholesterol synthesis
HMG-CoA reductase

(target of statins)
How many NET ATP are produced by glycolysis?
+2 net
How many NET ATP are produced by aerobic respiration per cycle?
+30-32 net ATP
a-ketoglutarate is an intermediate in the TCA cycle

in what way can hyperammonemia cause an a-KG deficiency that inhibits the TCA cycle?
a-KG is required for transfer of waste nitrogen to urea for excretion; hyperammonemia can cause a-KG depletion due to increased demand in nitrogen disposal pathway.
in what organs does glycolysis/ATP production use the *malate-aspartate* shuttle?
heart, liver
in what organ does glycolysis/ATP production use the *glycerol-3-phosphate* shuttle?
muscle
NADPH is a product of this metabolic pathway
Hexose-monophosphate (HMP) shunt
This nicotinamide compound is used in *catabolic* processes to carry away reducing equivalents
NAD+ (--> NADH)
This nicotinamide compound is used in anabolic processes (steroid and FA synthesis) as a supply of reducing equivalents
NADPH
Name four important cellular processes for which NADPH is essential:
1. anabolic processes
2. respiratory burst (ROS release from immune system cells)
3. P-450 system metabolism
4. Glutathione reductase (important antioxidant)
hexokinase and glucokinase perform the same function, but in different places - where is hexokinase found vs glucokinase?
hexokinase - ubiquitous
glucokinase - liver and B cells of pancreas

"G for GI only"
After a meal, glucokinase performs this action to sequester excess glucose in the liver
phosphorylates excess glucose
does hexokinase have feedback inhibition?
inhibited directly by glucose 6 phosphate
does glucokinase have feedback inhibition from any downstream compounds?
no direct feedback inhibition
glucokinase (liver) is induced by this compound
insulin
What is the difference between glucokinase and hexokinase in terms of affinity (Km)/capacity (Vmax) for glucose?
glucokinase: low affinity, high capacity
hexokinase: high affinity, low capacity
write out the net glycolysis reaction
Glucose + 2Pi + 2 ADP + 2 NAD+ --> 2 pyruvate + 2 ATP + 2 NADH + 2 (H+) + 2 H2O
What is the function of fructose-2,6-bisphosphate?
Accelerates conversion of F-6-P to F-1,6-bisP

(rate limiting step in glycolysis)
what is the function of fructose bisphosphatase 2?
converts F-2,6-bisP to F-6-P

(active when fasting)
what is the function of phosphofructokinase 2?
converts F-6-P to F-2,6-bisP
fructose bisphosphatase 2 is upregulated in the fasting state. what compound is responsible for this change?
inc glucagon
phosphofructokinase-2 is upregulated in the fed state. what compound is responsible for this change?
insulin
the pyruvate and a-ketoglutarate dehydrogenase complexes have 3 enzymes that require the same five cofactors:
1. pyrophosphate
2. FAD
3. NAD
4. CoA
5. Lipoic acid
How does ARSENIC disrupt normal cell metabolism?
interferes with lipoic acid, one of the cofactors of the pyruvate- and a-KG dehydrogenase complexes
pyruvate dehydrogenase deficiency --> increased conc of pyruvate and alanine --> (metabolic disturbance?)
lactic acidosis
Given what you know about the five cofactors for pyruvate and a-KG dehydrogenase complexes, why might an alcoholic be deficient in these enzymes?
Alcoholics: thiamine (B1) deficiency
Pyruvate --> lactate --> _______
Cori cycle
Pyruvate --> Acetyl CoA --> _______
TCA cycle
Pyruvate --> Oxaloacetate --> _______ (x2)
-TCA cycle
-gluconeogenesis
Pyruvate --> Alanine --> glutamate --> _______
urea cycle
3x irreversible enzymes of TCA cycle
-citrate synthase
-isocitrate dehydrogenase
-aKG dehydrogenase
Where do TCA cycle reactions occur?
mitochondria
electrons carried by NADH from glycolysis and the TCA cycle can enter mitochondria by either of these two pathways
malate-aspartate shuttle
glycerol-3-phosphate shuttle
A concentration gradient of this ion, produced by the electron transport chain, drives formation of ATP
H+
Protein in the ETC where NADH donates electrons recovered from glycolysis/TCA cycle
Complex I
Protein in the ETC where FADH2 donates electrons recovered from glycolysis/TCA cycle
Complex II (succinate dehydrogenase)
How do the following compounds interfere with normal oxphos?

Rotenone, CN-, antimycin A, CO
electron transport inhibitors --> decreased H+ gradient --> blocked ATP synthesis
How do the following compounds interfere with normal oxphos?

Oligomycin
ATPase inhibition --> increased proton gradient, no ATP
How do the following compounds interfere with normal oxphos?

2,4-dinitrophenol, aspirin, thermogenin
Uncoupling agents --> inc permeability of inner mitochondrial membrane --> decreased proton gradient, increased O2 consumption --> no ATP synthesis, but HEAT produced
Name the four irreversible enzymes in gluconeogenesis

"Pathway Produces Fresh Glucose"
Pyruvate carboxylase
PEP carboxykinase
Fructose-1,6-bisphosphatase
Glucose-6-phosphate
Pyruvate carboxylase requires these two cofactors
biotin, ATP

(converts pyruvate --> oxaloacetate)
pyruvate carboxylase is found where?
mitochondria
PEP carboxykinase is found where?
cytosol
what is the function of PEP carboxykinase?
oxaloacetate --> phosphoenol pyruvate
what is the function of fructose 1,6 bisphosphatase?
converts F-1,6-bisP --> F-6-P
Gluconeogenesis primarily occurs in this organ
liver
three primary substrates for gluconeogenesis
lactate, glycerol, glucogenic amino acids
What is the purpose of the hexose monophosphate shunt?
HMP shunt...

-produces NADPH from glucose-6-phosphate
-ribose for nucleotide synthesis

No ATP used or produced
Two distinct phases of the HMP shunt
oxidative
non-oxidative
oxidative reaction of HMP shunt produces (x3)?
CO2, NADPH, ribulose-5-P
non-oxidative reaction of HMP shunt produces (x3)?
ribulose-5-P, G3P, F6P

(NADPH only produced by oxidative reaction)
The respiratory burst involves the action of this membrane protein
NADPH oxidase
What two cell types have a respiratory burst?
neutrophils, macrophages
Respiratory burst produces this product
reactive oxygen species
NADPH oxidase deficiency --> no respiratory burst --> (disease?)
chronic granulomatous disease
NADPH is necessary for the reduction of this compound, which is used by the cell to detoxify free radicals and peroxides
glutathione
Why does a glucose-6-phosphate dehydrogenase deficiency lead to hemolytic anemia?
G6PD is necessary for the HMP shunt, which produces NADPH.

With less NADPH, RBC's have poor defense against free radicals --> membrane damage --> cell lysis
oxidized Hgb precipitated within RBC's
Heinz bodies
microscopic appearance of RBCs after phagocytic removal of Heinz bodies by splenic macrophages
bite cells
First enzyme in the pathway by which fructose enters glycolysis
fructokinase
Disease in which fructokinase (first enzyme in the pathway by which fructose enters glycolysis) is defective?
essential fructosuria

(benign, asymptomatic condition - fructose appears in blood or urine...)
[Fructose-1-P --> DHAP + glyceraldehyde]

A deficiency in what enzyme disrupts the above reaction?
Aldolase B
In fructose intolerance (aldolase B deficiency), what is the biochemical mechanism of inhibition of gluconeogenesis and glycogenolysis?
No aldolase-B --> F-1-P accumulates --> decrease in available phosphate --> inhibition of reactions (as above)
a person who is fructose intolerant has a deficiency in aldolase B. treatment involves restricting intake of these two carbohydrate compounds:
-fructose
-sucrose (= glucose + fructose)
galactose --(enzyme A)--> gal-1-P --(enzyme B)--> G-1-P

What are enzymes A and B?
A: galactokinase
B: uridyl transferase
galactose --(galactokinase)--> gal-1-P

If a person has a galactokinase deficiency, what happens to all that accumulating galactose?
galactose --(aldose reductase)--> galactitol

increased concentrations of galactose and galactitol cause poor growth, jaundice, infant cataracts, mental retardation
galactokinase deficiency: what carbohydrates must be restricted to avoid complications of the disease?
-galactose
-lactose (=glucose + galactose)
In conditions of extremely high blood glucose, the body may try to trap glucose in cells as this compound, the alcohol counterpart of glucose.
sorbitol
Glucose --(enzyme A)--> sorbitol --(enzyme B)--> fructose

What are enzyme A and B?
A: aldose reductase
B: sorbitol dehydrogenase
In conditions of extremely high [glucose] in blood, why are Schwann cells, the lens, the retina, and the kidneys at risk of damage?
cells in these structures possess aldose reductase, meaning that they convert glucose to sorbitol

however, they have no mechanism to convert sorbitol to fructose, so sorbitol accumulates --> influx of H2O --> osmotic damage
In conditions of hyperglycemia, what organs are most susceptible to damage?
glucose --(aldose reductase)--> sorbitol accumulation --> osmotic damage

lens of eye (cataracts), retina (retinopathy), Schwann cells (peripheral neuropathy)
Which optical isomer of amino acids is found in proteins?
L amino acids
Name the four glucogenic amino acids
Met Val Arg His
Name the four glucogenic/ketogenic amino acids
Ile Phe Trp Thr
Name the two ketogenic AAs
Leu Lys
Acidic amino acids (negatively charged at body pH) x2
Asp Glu
Basic amino acids x3 = positively charged at body temp
Arg, Lys, His
Most basic amino acid
Arg
These two amino acids are esp concentrated in histone proteins
Arg, Lys

histones must be positively charged to bind negatively charged DNA
Mnemonic for TCA cycle

"Our City Is Kept Safe And Sound From Malice"
Oxaloacetate --> citrate --> isocitrate --> a-ketoglutarate --> succinyl CoA --> succinate --> fumarate --> malate
What is the purpose of the urea cycle?
amino acid catabolism --> production of excess NH4

Urea cycle: excess NH4 converted to urea for excretion in urine
Rate limiting enzyme in the urea cycle:

CO2 + NH4 --(enzyme?)--> carbamoyl phosphate
carbamoyl phosphate synthetase I

(CPS II is rate-limiting for de novo pyrimidine synthesis)
Four compounds cycling in the urea cycle:
citrulline --> arginosuccinate --> arginine --> ornithine

(FA p. 105 for diagram)
Two compounds which constantly feed into the urea cycle
carbamoyl phosphatase, Asp

(FA p. 105 for diagram)
Which compound entering the urea cycle contains the excess nitrogen?
carbamoyl phosphatase

(FA p. 105 for diagram)
enzyme that transports carbamoyl phosphate out of the mitochondrion as part of the urea cycle
ornithine transcarbamoylase
most common urea cycle disorder
ornithine transcarbamoylase (OTC) deficiency
What is interesting about the inheritance pattern of OTC deficiency vs other urea cycle deficiencies?
OTC deficiency: XLR
other urea cycle deficiencies: AR
What are the metabolic consequences of OTC deficiency?
excess carbamoyl phosphate --> excess orotic acid (blood, urine)

can't eliminate nitrogenous waste --> ammonia intoxication
see p. 106 in FA 2011 - write out each of the pathways for derivatives from important amino acids
...
amino acid precursor to tyrosine
Phe
tyrosine converted to DOPA by this enzyme
tyrosine hydroxylase
DOPA converted to dopamine by this enzyme
DOPA decarboxylase
DA --(enzyme?) --> NE
dopamine B-hydroxylase
NE --(enzyme?)--> EPI
phenylethanolamine N-methyl transferase (PNMT)
homovanyllic acid is a breakdown product of this compound
dopamine
vanillylmendelic acid is a breakdown product of this compound
NE
metanephrine is a breakdown product of this compound
epinephrine
What is the general function of SAM (s-adenyl methionine)?
methyl donor
What is phenylketonuria?
Absence of the enzyme that converts [Phe --> Tyr]

Result: must decrease Phe intake, Tyr becomes essential
Inheritance of phenylketonuria?
AR
What is the treatment for phenylketonuria?
Phe --||--> Tyr

decrease Phe consumption
increase Tyr consumption (Tyr becomes essential)
two enzymes that break down catecholamines
MAO, COMT