Candyman's Usmle Biochem

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Amino acids necessary for purine synthesis

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glycine, aspartate, glutamine

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Inhibits ribonucleotide reductase

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Hydroxyurea blocks ribonucleotides --> deoxyribonucleotides

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Inhibits thymidylate synthase

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5-FU blocks dUMP --> dTMP
-Requires Me-THF
-Regeneration of Me-THF requires dihydrofolate reductase

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Inhibits de novo purine synthesis

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6-MP

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Inhibits dihydrofolate reductase

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Methotrexate
Trimethoprim (in bacteria)

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Defect in nucleotide excision repair

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Xeroderma pigmentosum (AR)
-can't repair UV-induced thymine dimers
-photosensitivity
-prone to melanoma and other cancers

Cockayne's Syndrome (AR)
-cells unable to respond to UV dmage
-accelerated aging of cells, bird-like facies

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Defect in mismatch repair genes

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HNPCC (Lynch Syndrome) -- AD
-mutations in MSH2, MLH1

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mRNA start codon

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AUG (methionine)

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mRNA stop codons

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UGA, UAA, UAG
"U Go Away"
"U Are Away"
"U Are Gone"

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RNA processing

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Occurs w/in nucleus:
1. 5' cap (Gpppp)
2. 3' Poly-A tail
3. Splicing (remove non-coding introns) via spliceosome

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Steps of splicing

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1. Primary transcript (pre-mRNA) combines with snRNPs and other proteins to form spliceosome
2. Lariate-shaped intermediate generated
3. Lariate released to remove intron and join exons --> mRNA

Exon - GU...A...AG - Exon

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TSGs that inhibit G1 --> S progression

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Rb and p53

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Rough ER

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Site of synthesis of secretory proteins
-Goblet cells of SI (synthesize mucus)
-Plasma cells (synthesize ab's)
-Nissl bodies in neurons (synthesize peptide NTs)

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Smooth ER

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Site of steroid synthesis and detoxification of poisons
-liver hepatocytes
-adrenal cortex

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Vesicular trafficking proteins

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COPI: retrograde, Golgi --> ER
COPII: anterograde, RER --> cis-Golgi
Clathrin:
trans-Golgi --> lysosomes
Receptor mediated endocytosis

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I-cell disease

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= Inclusion-cell disease
-inherited lysosomal storage disease
-failure of addition of mannose-6-phosphate to lysosomal proteins --> enzymes are secreted outside cell i/o targeted to lysosome
-coarse facial features, clouded corneas, restricted joint mvt
-often fatal in childhood

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-coarse facial features, clouded corneas, restricted joint mvt
-often fatal in childhood

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I-cell disease
-inherited lysosomal storage disease
-failure of addition of mannose-6-phosphate to lysosomal proteins --> enzymes are secreted outside cell i/o targeted to lysosome

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Microtubule structure & fxn

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-Composed of tubulin dimers, each bound by 2 GTP
-Incorporated into flagella, cilia, mitotic spindles
-Grow slowly, collapse quickly
-Involved in axonal transport in neurons
-Molecular motor proteins (dynein, kinesin)

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Molecular motor proteins

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Transport cargo along microtubules
-Dynein - retrograde transport (+ --> -)
-Kinesin - anterograde transport (- --> +)

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Drugs that act on microtubules
-anti-helminthic
-anti-fungal
-anti-cancer
-anti-breast cancer
-anti-gout

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-Mebendazole, thiabendazole (antihelminthic)
-Griseofulvin (antifungal)
-Vincristine, vinblastine (anti-cancer)
-Paclitaxel (anti-breast cancer)
-Colchicine (anti-gout)

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Chediak-Higashi Syndrome

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Microtubule polymerization defect --> decreased phagocytosis
-recurrent pyogenic infections, partial albinism, peripheral neuropathy

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Kartagener's Syndrome

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-Immotile cilia due to dynein arm defect
1. Recurrent sinusitis, bronchiectasis
2. Infertility
3. Situs inversus

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GFAP stain

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Neuroglial cells (especially astrocytes)

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Neurofilament stain

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Neurons

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Cytokeratin stain

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Epithelial cells

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Vimentin stain

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Connective tissue

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Desmin stain

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Muscle

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Na+/K+ ATPase inhibitors

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1. Ouabain (blocks K+ binding site)
2. Cardiac glycosides (digoxin, digitoxin)

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Type I collagen

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BONE, tendon, skin, cornea

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Type II collagen

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CARTILAGE, nucleus pulposus

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Type III collagen

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Reticulin, blood vessels, granulation tissue

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Type IV collagen

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Basement membrane

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Collagen synthesis

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1. RER -- Synthesis of preprocollagen (Gly-X-Y polypeptide)
2. ER -- Post-translational hydroxylation of proline & lysine (requires vit C)
3. ER -- Post-translational glycosylation of lysine --> procollagen triple helix
4. Exocytosis & cleavage --> tropocollagen
5. Cross-linking --> collagen fibrils

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Ehlers Danlos Syndrome

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Faulty collagen synthesis (usually type III) causing:
-hyperextensible skin
-easy bruising
-hypermobile joints
-associated with berry aneurysms

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Osteogenesis Imperfecta (4 features)

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Most common form is AD w/ abnormal type I collagen, causing:
-brittle bones-->multiple fractures
-blue sclerae due to translucent CT over choroid
-hearing loss due to abnormal middle ear bones
-dental imperfections due to lack of dentin

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Scurvy

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Vit. C deficiency --> inability to hydroxylate proline and lysine, causing:
-weakening of capillaries
-gum ulceration, tissue hemorrhage, anemia, poor wound healing, loose teeth, corkscrew hairs

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Alport's syndrome

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-X-linked recessive
-Results from abnormal type IV collagen
-Progressive hereditary nephritis and deafness

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Congenital collagen diseases

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Type I - Osteogenesis Imperfecta
Type II - ?
Type III - Ehlers Danlos Syndrome
Type IV - Alport's Syndrome

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Marfan Syndrome

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-Autosomal dominant disorder
-Defect in fibrillin gene (FBN1) --> absence of elastin-associated fibrillin
-bone elongation, arachnodactyly, hypermobile joints, lens dislocation
-cardiac abnomalities (MVP), aortic dissection/rupture, aortic regurgitation, berry aneurysm

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Which cyclins correspond to which phases of the cell cycle?

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G1 - Cyclin D increases
S - Cyclin E increases
G2 - Cyclin B/A increases
Mitosis

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Which anti-cancer drugs block nucleotide synthesis? (3 drugs)

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1. Block thymidine synthesis
-5-FU inhibits thymidylate synthase
-Methotrexate inhibits DHF reductase
2. 6-MP blocks de novo purine synthesis

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Which anti-cancer drugs cross-link DNA? (2 drugs)

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1. alkylating agents
2. cisplatin

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Which anti-cancer drugs intercalate DNA? (2 drugs)

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1. dactinomycin
2. doxorubicin (adriamycin)

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Which anti-cancer drugs inhibit topoisomerase II? (1 drug)

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1. Etoposide

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Which anti-cancer drugs interfere with microtubule formation and/or disassembly? (3 drugs)

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1. Vinca alkaloids (vincristine, vinblastine) block microtubule formation
2. Paclitaxel blocks microtubule disassembly

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Leucovorin (folinic acid) rescue is effective with which drug?

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MTX ... b/c it provides an exogenous source of THF, thereby overwhelming block of DHF reductase.

NOT effective with 5-FU

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Blocks de novo purine synthesis. Activated by HGPRTase.

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6-MP

Note: metabolized by xanthine oxidase; thus, increased toxicity with allopurinol

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Alkylating agents? (3)

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1. Cyclophosphamide, ifosfamide
2. Nitrosoureas (carmustine, lomustine, etc.)
3. Busulfan

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Used in colon cancer and other solid tumors

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5-FU

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Used to treat brain tumors (including glioblastoma multiforme)

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Nitrosoureas (carmustine, lomustine, semustine, etc)
-alkylating agents
-cross BBB
-Can cause CNS toxicity

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Used to treat testicular, bladder, ovary, and lung carcinomas

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Cisplatin, carboplatin
-cross-link DNA
-can cause nephrotoxicity and acoustic nerve damage

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Used to ablate bone marrow b/f HSC transplant

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Busulfan
-alkylates DNA
-can cause pulmonary fibrosis, hyperpigmentation

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ABVD combination for Hodgkins lymphoma

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Adriamycin (doxorubicin) = intercalating agent, generates free radicals --> breaks
Bleomycin = generates free radicals --> breaks
Vinblastine = blocks polymerization of microtubules
Decarbazine = alkylating agent

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Used in childhood tumors (Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma)

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Dactinomycin (Actinomycin D)

"Children ACT out"

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Side effect of bleomycin

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Pulmonary fibrosis, skin changes

Other drugs that cause pulmonary fibrosis: amiodarone,

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Inhibits ribonucleotide reductase

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hydroxyurea
-used in melanoma, sickle cell disease (increased HbF)

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Inhibits topoisomerase II --> increased DNA degradation

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Etoposide

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Used in estrogen receptor + breast cancers and osteoporosis

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SERMs = receptor antagonists in breast, agonists in bone
1. Tamoxifen (may increase risk of endometrial carcinoma b/c endometrial partial agonist)
2. Raloxifene (does nOT cause endometrial carcinoma b/c endometrial antagonist)

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Monoclonal antibody against HER-2 (erb-B2)

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Trastazumab (herceptin)
-cardiotoxicity

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Used in CML, GI stromal tumors

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Imatinib (Gleevec)
-BCR-ABL fusion tyrosine kinase inhibitor

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Used in ovarian and breast carcinomas

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Paclitaxel, -taxols
-hyperstabilizes polymerized microtubules so they cannot break down (i.e. anaphase cannot occur)

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What are psammoma bodies and in which tumors are they found?

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PSaMMoma bodies:
-Form around single necrotic cells
-Small laminated, concentric spherules containing calcium
-Found in...
Papillary carcinoma of thyroid
Serous papillary cystadenocarcinoma of ovary
Meningioma
Mesothelioma

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Helps to improve appetite in pts receiving anti-neoplastic therapy

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Megestrol acetate