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How is dietary folate converted to an active cofactor?

Folate comes from diet

Folate has poly-glutamate tail that is digested down to mono-glutamate in gut by Dihydrofolate reductase (DHFR)

Folate is reduced to N5-methyl tetrahydrofolate in intestinal epithelial cells by DHFR

FH4 + formate --> N10 formyl FH4


What is the pathway from THF to methylcobalamin?

THF + formate --> 10-formyl THF

reduced to

5,10 Methenyl THF

reduced to 

5,10- Methylene THF

reduced to (irreversible methyl trap)

5-Methyl THF (+ cobalamin) --> methylcobalamin


What amino acids can help produce folate intermediates?

THF + histidine --> 5,10-methenyl THF

THF + serine --> 5,10-methylene THF + glycine

*Serine is the most important contributor to the one carbon pool

*Serine, glycine, choline, histidine, and formate contribute to the one carbon pool

*Thymidine nucleotide, purine bases, methionine, and SAM are PRODUCTS of one carbon donations


Describe the one carbon transfer in thymidine nucleotide synthesis and what might be a good anti-cancer therapy

Thymidylate Synthase(TS) reduces Methylene THF to methy during its transfer to dUMP to make dTMP.

This leaves THF in DHF, which then gets reduced to THF by DHFR which can then accepts another one carbon group from serine (hydroxymethlytransferase) to recycle methylene THF 

The cycle continues producing more dTMP

**Can inhibit TS or DHFR to target pathway in anti-cancer therapy**


How is dietary Cobalamin converted into a cofactor?

aka Vitamin B12

Dietary B12 first binds to R-binder proteins secreted in the stomach

As R binders are digested, they bind intrinsic factors

This complex is taken up by intestinal epithelial cells and is tranported in the blood as a complex with transcobalamin II protein


What are the two Cobalamin Reactions?

1. Adenosyl cobalamin is a cofactor for the rxn where methylmalonyl CoA mutase convers methylmalonyl CoA (from branched/ odd chain A.A.) to Succinyl Co A in order to enter TCA cycle


2. Methionine synthase catalyzes the transfer of methy from methylcobalamin to homocysteine to make methionine.

Methione can vind adesoine nucleoside to become SAM. SAM donates methyl group to numerous substrate including precursors to neurtransmitters


Spinda bifida

Folate deficiency

Neural tube development disorder


Heredity Folate Malabsorption

inherited mutation in the proton coupled folate transporter (PCFT)

which is main transporter for dietary folate

Causes a functional folate deficiency despite adequate dietary folate


Megoloblast anemia

folate deficiency

fewer red blood cells, but are larger than normal

lack of thymidine nucleotides delays DNA synthesis, cell mass grows but genome doesn't replicate, delay in cell division


Pernicious anemia

(megaloblastic anemia + neuro problems)

B12 deficiency

Auto immune disease attack parietal cells, intrisic factor can't interact with cobalamin so can't get uptake

Symptoms: megaloblastic anemia, big beefy tounge, autoimmue gastritis, and NEURO EFFECTS (demylination)



mutations in methionine synthase

linked to cardiovascular and neurological problems


Why is folate metabolism a treatment for cancer?

Cancer cells divide rapidly and have high requirement for deoxynucleotides

Methotrexate is a folate analog that inhibits DHFR

5-FLuorouracil is a uracil analog that inhibits TS

In addition to cancer cells these drugs also kill other rapidly dividing cells- blod cells, epithelial cells, and hair follicles


What is the methyl trap hypothesis?

The only metabolic fate of 5-methyl THF is to loose its methyl to cobalamin

In dietary or functional deficiency of cobalamin, folate becomes "trapped" as 5-methyl THF thus unable to particpate in other one carbon transfers

*Cobalamin deficiency results in a functional folate deficiency becase all folate gets trapped as 5-methyl THF


What are common properities of infectious disease?

Micro organisms

acute onset


immune response


Common modes of transmission of infectious diseases?

Person to person: air borne, direct contact, sexual transmission

Zooenotic (vector borne)

Soil Borne

Common Source (contaminated water supple, food borne)


What did the germ theory of disease demonstrate?

demonstrated link between microbs and infectious disease


What are Koch's Postulates?

1. Suspect pathogen must be in ALL disease cases, and absent in healthy animals

2. Grow pathogen in pure culture **

3. Cells from pure culutre must cause disease in healthy animal**

4. Suspected pathogen must be re-isolated and shwon to be the same as orginal pathogen

Obstacles: need animal model, and some stuff dificult to grow in culutre


The gene theory of disease

Microbial infections that lead to disease can be viewed as an arms race for replication that in the purest sense is related to the survival of one set of genetic information at the expense of another


Griffith's Experiment

Smooth (capsule)/ Rough (no capusle)

Live S cells killed, Dead S cells didn't

Live R cells didn't

heat killed S cells + live R cells killed

*virulence factors- any molecule of a microogransim that aids in its ability to establish and maintain pathogenic infection


Common Bacterial morphologies





Budding/ appendage bacteria (stalk/ hypha)

Filamentous bacteria


How do you perform and interpret a Gram Stain?

Prepare smear: spread culutre in thin film over slide, dry

Heat fix and stain with crystail violet (all cells purple)

Add iodine (crystalizes violet into wall)

Decolorize with alcohol (gram+ are purple, gram- are colorless)

Counter stain with safranin (gram+ are purple, gram- are pink)


Differences found in prokaryotic and eukaryotic cell structures


Aggregated mass of DNA (nucleoid)
Cell wall/ peptidoglycan
No membrane bound organelles
DNA one chromosome, circular, lack histones
Cell division by fission or budding



Membrane-enclosed nucleous


No cell wall

Membrane bound organelles

DNA multiple chromosomes, linear, contain histones

Cell division by mitosis or meiosis



Process of binary fission

cell elongation, septum formation, completion of septum, formation of walls, cell seperation


**Populations grow EXPONENTIALLY**


3 enzymes needed for Peptidoglycan Synthesis


Transglycosylase (to link sugars)

Transpeptidase to like peptides

*Autolysis occurs unless new cell wall precursors are spliced into existing peptidoglycan to prevent a break in peptidoglycan integriaty as splice point

**Penicillin binds and block activity of transpeptidase


Describe Glycogen Structure

Glycogen is a polymer of glucose

Two types of carbon carbon bonds in glycogen

(1:4) linear chains

(1:6) make branch points

Glycogen syntase adds UDP-glucose to chain until 11 units long

Branching enzyme cleaves a piece of chain off and attaches it in a 1:6 glycosidic linkage- both braches are further extended


Glycogens function in liver and and other tissues?

Glycogen is used as a glucose storage for most cell types

In heart & Skeletal- intracellular glucose buffer, buffer for glucose 6-phosphate for use within cells (depends on how much getting from blood, and how much cell is doing). When cleaving glycogen its use is for ONLY that cell

Liver- Serves as glucose buffer for BLOOD, regulates whole body glucose homeostasis. Used for hepatocyte but is also excreted in blood


Enzymes in glycogenogenesis

Glycogen Synthase- adds UDP glucose on to glycogen core

4:6 transferase (branching enzymes) cleaves a piece of chain off and attaches it in a 1:6 glycosidic linkages

Both branches extended


Advantages of branching in glycogen?

Increases solubility

Make more active ends so glycogenolysis and glycogenesis can happen rapidly


Enzymes in glycogen degradation

Glycogen phosphorylase- cleaves unites of glucose from glycogen chains and adds inorganic phosphate to make glucose-1-phosphate (but can't cleave glucose with in four units of branch point)

Debranching enzyme- two activities

(4:4 transferase activity) cleaves a 1:4 bond and transfers 3 glucose units to the end of another chain in 1:4 bond

(alpha-1,6-glucosidase activity) hydrolyzes the remaing glucose's 1:6 bond to release glucose


Regulation of glycogen metabolism Fed vs Fasted state

In Fed State: both are UNphosphorylated, glycogen phosphorylase is inactive, glycogen synthase is active

In Fasted State: both are PHOSPorylated, glycogen phosphorylase is active, glycogen synthase is inactive


Insulin (hepatocyte and skeletal) how it regulates glycogen metabolism

Insulin activates (phosphorylates) protein phosphatase-1 which dephosphorylates glycogen synthase (activating it)

Inhibits (phosphorylates) glycogen synthase kinase-3 (inactiving it)


Glucagon (hepatocyte only)/ Epinephrine beta regulation in glycogen metabolism

cAMP --> PKA --> phosphorylates glycogen synthase (inactive) and glycgoen phosphorylase kinase (active) --> which then phosphorylates glycogen phosphorylase (acitve) --> glycogenolysis --> GLUCOSE


Glycogen regulation in skeletal muscle (non-hepatocyte)

No glucagon receptor

Nerve impulse--> Ca --> Ca/calmodulin dependent kinase --> phosphorylates glycogen phosphorylase kinase --> phosphorylase  glycogen phosphorylase (active)

Work --> AMP --> AMPkinase --> glycogen phosphorylase kinase (active) --> glycgoen phosphorylase (active)

Insulin --> phosphorylates protein phosphatase-1 (active) and glycogen synthase kinase 3 (inactive) --> protein phosphatase then dephosphorylates glycogen synthase (active)



mutation/ deficiency in glycogen synthase

Normal glucose tolerance, variable clinical presentation of exercise intolerance, cardia and muscle hypertrophy



deficiency in glucose 6- phosphatase (can't make all the way back into glucose to leave cell)

Fast hypoglycemia, lactic acidosis

hepatomegaly due to glycogen accumulation

hyperuricemia and hyperlipidemia

Treatment: avoid fasting by frequent feeding, uncooked cornstarch



Deficiency of 1,6-glucosidase activity of debranching enzyme

*can make glycogen when eating too many carns, but can't break it down all the way in fasting state

GSD IIIa : affects liver and muslce

GSDIIIb: only affect liver

Symptoms: fasting hypoglycemia, ketoacidosis, hyperlipidemia, heptomegaly with high ALT/AST

Treatment: frequent high carb meals



mutation in 4:6 transferase activity of branching enzyme, longer than normal brances, liver failure




mutations in muscle glycogen phosphorylase

late childhood onset of exercise intolerance, myoglobinuria after exercie

Increased creatine kinase, exaggerated increase of creatine kinase and ammonia after exercise (can't utilize glycogen, swithcing to AA metabolism)

Avoid exercise


Describe various structures associated with human and bacterial viral pathogens

• Genome- ssRNA, dsRNA, ssDNA, dsDNA
• Capsid- protein coat around genome (capsomere), protects nucleic acids, and is responsible for binding host cells if not enveloped
• Envelope- (some, not all viruses) glycoproteins, function is to bind and mediate entry into host cells. “Naked viruses” have no envelope
• Tegument- space between capsid and envelope,  protein dense region that surrounds capsid, holds them together
• Virion- infectious particles produced


Compare the exponential growth of bacterial cells with the one-step growth cycle used during viral replication.

• Latent period- externally doesn’t seem like anything is happening, but really transcription/ translation/replication are occurring
o Good period for attack
• Then get rapidly release of virions in ONE STEP (lots of viruses at ONE time)
• Those virions can go off and affect other cells


Describe the plaque assay procedure – how it’s performed and how it’s useful in the quantification of viral particles

• Plaque Assay- one of the most accurate ways to measure virus infectivity and infectious viral particle numbers
• Procedure
o Mixture containing molten top agar, bacterial cells, and diluted phage suspension
o Pour mixture onto solidified nutrient agar plate
o Let solidify, sandwhich of top again and nutrient agar
o Incubate
o Results are phage plaques on a lawn of host cells


Describe each of the following terms as they relate to human viruses and the cells that they infect: transformation, lysis, persistence, latent, reactivation, cell fusion

• Transformation- virus transforms cell into tumor cell
• Lysis- death of cell and release of virus
• Persistence- Slow release of virus without cell death
• Latent- virus present but not replicating
• Reactivation- may revert to lytic infection?
• Cell fusion- didn’t go over?


Describe each of the following terms as they relate to bacteriophages and the cells that they infect:  lysis, lysogeny, virulent, temperate, prophage

• Temperate virus- can go lytic or lysogenic?
• Lysis- viral DNA replicates, coat proteins synthesized, virus particle assembled, host cell is lysed open to expose contents
• Lysogeny- viral DNA is integrated into host DNA, lysogenized cell under goes cell division replicating the prophage (integrated genome)
• Prophages conferring virulence factors


Baltimore classification system


dsDNA (+) genome

classical semiconservative replication

Example: Herpres virsues- uses host DdRp to make mRNA


Baltimore Classification System


ssDNA (+) genome

dsDNA intermediate

classical semiconservative, discard (-) strand for packaging


Baltimore classification system


dsRNA (+) genome

transcription of minus strand to make (+) strand


Baltimore Classification System


ssRNA (+) genome (can be used directly as mRNA)

makes ssRNA (-) and transcribes this to give ssRNA (+) genome

Example: Polio/ Picornaviruses

*needs RdRp, so must do some translation before genome replication

one long ssRNA strand gets cut after translation into individual proteins


Baltimore Classification System


ssRNA (-) genome

makes ssRNA (+) and transcribes this to give ssRNA (-) genome

Example: Influenze/ orthomyoxyviruses

ssRNA (-) released into cytoplasm, transported to nucleous to steal caps and stuff

brings RdRp with it (attached to each segment of genome)


Baltimore Classification System


ssRNA (+) genome

transcribes (-) strand of dsDNA to replicate genome

(Reverse transcription)

Example: Retroviruses/ HIV

two copies of ssRNA (+) genome, plus RT and integrase in virion

integrase intergrates dsDNA into host genome


Baltimore CLassification system


dsDNA genome

transcription followed by reverse transcription


General Viral Replication Cycle


Penetration/ injection

Synthesis of nucleic acid and protein

Assembly and packagine



Identify properties which limit usefulness of a drug class and drugs within a class        (toxicity)

• Selective Toxicity- antibiotics need to injure the invading organism while causing minimal adverse effects to the host
• Toxicity- can be due to
o Extension of mechanism of action
• Trimethoprim can inhibit folate metabolism in humans as well as bacteria resulting in bone-marrow
o Unintended consequences
• Vancomycin can stimulate histamine release (red man syndrome)
o Impaired drug metabolism
• Renal failure or hepatic insufficiency result in direct antibiotic effects or drug interaction


Differentiate between prophylactic, pre-emptive, empiric, suppressive, and definitive therapy

• Prophylactic- treating individuals at a high risk of developing an infection to prevent an infection from developing
• Pre-emptive- lab test indicate organism is present but patient is not symptomatic
• Definitive Therapy- pathogen identified (monotherapy, narrow spectrum)
• Suppressive Therapy- after initial disease is controlled, therapy is continued to prevent recurrence


Categorize drugs as bactericidal and bacteriostatic and explain when you would prefer to use bactericidal drugs

• Bacteriostatic- limits growth and if removed the organism can grow again. Usually successful because allows immune system to catch cup
• Bactericidal- 99.9% reduction in bacterial inoculums with 24 hr period of exposure
• **many bactericidal drugs do not work well if the cells are not actively diving
• ** persons with depressed immune systems would not be good canidates for bacteriostatic drugs


Identify patient factors which affect drug absorption, distribution, metabolism, and excretion

• absorption- movement of drug into vascular system, variability in how well drugs are absorbed from the gut
• Distribution- transfer of drug from vascular system to tissue
• Metabolism- transformation of a compound into metabolites (liver) often inactivates or eliminates the drug BUT prodrugs become active
• Excretion- removal of the drug from the body through urine or feces


Identify mechanism through which drugs develop resistance

• Intrinsic resistance- absence or inaccessibility of the target of the drug action
• Acquired drug resistance- genetic variability exists in the population and resistant forms are able to preferential grow in the presence of the antibiotic
o Variability may result from errors during replication
o Transformation of external DNA
o Bacteriophage can introduce new DNA through transduction
o Conjugation- transfer of R plasmid containing several resistance determinant genes


General potential targets for antibiotics

i. Cell wall synthesis (peptidoglycan)
ii. Nucleic acid synthesis
iii. Cell membrane integrity
iv. Metabolic pathways (folate biosynthesis)
v. Protein Synthesis


Antibiotic Drug Resistance- what causes it? and what are some of the mechanisms?

Acquired Drug Resistance- genetic variability exists in the population and resistant forms are able to preferential grow in the presence of the antibiotic **UNDERSTAND DRUG ITSELF IN NOT CAUSING RESISTANCE**

a. Drug enters cell but efflux pump ejects it
b. Drug-inactivating enzyme- enzyme modifies drug that inactivates it
c. Alteration in target molecule
d. Decreased uptake


Purine Synthesis

phosphoribosyl amidotransferase transfers an amine from glutamine to PRPP

Add glycine to make glycinamide ribosyl 5-phosphate

Carbon, nitrogen are added from THF, CO2, glutamine, and aspartate to form inosine monophosphate (IMP)

To make AMP, asaprtate bonds to IMP --> adenyloscuccinate, then fumarate is cleaved off to make AMP

To make GMP, IMP is oxidized to xanthine monophophate. Amine group is transferred from glutamine.

AMP and GMP are phosphorylated to make adenosine triphosphate and guanosine triphosphate


Describe 3 mechanisms by which bacteria can cause disease

1. Toxicity- producing toxins

2. Host immune response- repsonse of the host to bacteria

3. Colonization/ proliferation


Compare the properities of bacterial endotoxins and extoxins

Exotoxins- not part of the structure, released into enviornment: heat labile, specific mode of action, high toxicity, highly immunogenic

Endotoxins- integeral part of the structure itself, not excreted

(Example- LPS): heat stable, general mode of action, low toxicity, poor immunogen, induces fever


Describe three layers of the immune system.

Physical Barrrier- skin, mucous, epithelial layers, normal flora etc.

Innate Immune System- recognizes forgien particles non specifically, mediated by phagocytosis, recognizes PAMPs, complement, interferons (dendritic cell, marcophage, neutrophil, mast cell)


Adaptive Immune System- inducible, needs to learn how to recognize specific pathogens, has memory, takes time to develop (Antigen, BCR, antibody, TCR)


Cytolytic toxins

Exotoxin, makes holes in membranes surrounding cell. Cause efflux of cytoplasmic components, influx of extracellular components



 Hemolysins- type of cytolytic toxin that affects redn blood cell
1. Alpha hemolytic- produces hemolysins that damages but doesn’t destroy red blood cells
2. Beta hemolytic- produces hemolysins completely destroys red blood cells
3. Gama hemolytic- does not produces hemolysin


AB toxins

- Exotoxin, proteins excreted with two different modes of action, b = binding, a = activity
1. B domain binds to surface of susceptible cells, stays on outside
2. A  domain gets released into cytoplasm and shuts down something inside cell (shut down EF-2, which stops all protein synthesis)
EXAMPLES: E. COLI, Corynebacterium diphtheriae



exotoxin, secreted into small intestine, causes diarrhea



Exotoxin that can block release of excitation signal, (flaccid paralysis) or binds to inhibitory interneurons preventing release of glycine and relaxation of muscle (Tetanus- rigid paralysis)



Exotoxin, foreign molecule that can exploit interaction between T-cell receptor and MHC class II molecules. Links T-cell and MHC class II receptors NON-SPECIFICALLY activates A LOT of T-cells, causes runaway massive whole body inflammation




Pathogenicity Island

prophage confers additional virulence genes to bacteria


Proliferation of innate immune system

bone marrow cell

myeloid precursor


Dendritic cell, macrophage, neutrophil, mast cells

(these sells have PRRs that recognize PAMPs)



Proliferation of Adaptive Immune System

Bone marrow stem cell

lymphoid precursor

B cell/ T cell

B Cells can divide into plasma cells (produce antibodies) and memory cells



serum proteins, overall goal is to control inflamation

Microorganism can spontaneously activate complement, results in opsonizaiotn and facilited up take of the coated microogranisms by phagocytes. 


Virulence Factors of Salmonella

1. Enterotoxin (diarrhea) (type of exotoxin excreted into small intestine)
2. Type 1 Fimbriae (enhances edherence)
3. Endotoxin in LPS layer (fever)- inherent of gram neg
4. Injectosome- ticks phagasome to take it into the cell
5. Siderophores- gets excreted into near surface environment and takes up Fe (steals Fe from cells) ramps up ability to utilize more complex metabolic pathways
6. Anti-phagocytic proteins induced by oxyR- prevent degredation by phagosomes
7. O antigen (inhibits phagocyte killing)
8. Cytotoxin (inhibits host cell protein synthesis, calcium efflux, adherence)
9. Flagellum (motility) 
10. H Antigen (adherence, inhibits phagocyte killing)
11. Vi capsule antigen- inhibits complement binding


  1. Describe the key features of the Hepatitis C virus (HCV) lifecycle that lead to both its recognition as a foreign pathogen and its ability to bypass the intracellular innate immune response.

• During replication Hep C makes a dsRNA intermediate.
• This dsRNA molecule is recognized by TLR3 a Toll-like receptor (PRR)
• The dsRNA binds to TLR3, which activates a signaling cascade, 
• Downstream IRF3 is phosphorylated, which forms a dimer and is transported to the nucleus
• IRF3 acts as a transcription factor for IFNB (interferon)?
• IFN-B protein turns on genes that set up an anti-viral state (i.e, shuts down metabolic pathways viruses need to survive, and slows down infection so immune system can catch up.
• If virus gets past TLR3, dsRNA can bind to RIG-I which binds MAVS, which activates NFkB → IFN-beta 
• Viral protein NS3/4A cleaves viral protein, but also destroys signaling pathway proteins so can’t produce interferon → don’t get intracellular innate immune response/ antiviral state


Understand how the production of type I interferons in conducted and how their production leads to the antiviral state inside the host.

• Small protein, important in cell signaling, limit the spread of viral infection by the INNATE system
• Type 1 interferons- are produced by cells that have become infected with a virus
• Typer 2- released by activated T 


Know the three types of viral associated pathogenesis.

1. Cytopathic effect: viral infection disrupts normal cell physiology
2. Host immune response: response of the host to the virus casues illness
3. Tumorigenesis: viral infection promotes uncontrolled proliferation of infected cells


Know the two types of fungal associated pathogenesis.

1. Overgrowth: spread of fungal infection is significant in the cause of illness
2. Host immune response: response of the host to the fungus casues illneess


Know the three types of protozoan associated pathogenesis.

1. Displacement: tissure displacement/ obstruction due to the growth of protozoa causes illness
2. Cytpoathic effect- intracellular protozoa infection disrupts normal cell physiology
3. Host immune response: response of the host to protozoa causes illness


Know the three types of heminth associated pathogenesis.

1. Displacemnt- tissue displacement/ obstruction due to the growth of helminth causes illness
2. Parasite/ Competition: helminth consumes host nutrition
3. Host immune response: response of the host to protozoa csuses illneess