USMLE - BioChem Part 1
An autosomal dominant disorder with incomplete penetrance, characterized by hamartomas in the CNS and retina, cutaneous angiofibromas (adenoma sebaceum), ash-leaf spots, seizures, mental retardation, mitral regurgitation, cardiac rhabdomyomas, renal angiomyolipomas, and increased risk of astrocytomas.
Tuberous Sclerosis
What kind of inheritance?
Manifestations?
Autosomal Dominant w/ incomplete penetrance
Harmatomas of CNS and Retina, Adenoma Sebaceum (cutaneous angiofibroma), Mitral Reg, Ash-Leaf Spots on skin, Cardiac Rhabdomyomas, Mental Retardation, Renal Angiomyolipomas and Renal Cysts, Seizures, Increased incidence of astrocytomas
Key Terms
Tuberous Sclerosis
What kind of inheritance?
Manifestations?
Autosomal Dominant w/ incomplete penetrance
Harmatomas of CNS and Retina, Adenoma Sebaceum (cutaneous angiofibroma), Mitral Reg, Ash-Leaf Spo...
Histones?
Charge
Amino Acids
What do they form?
What ties it together?
Positively charged
Lysine and Arginine
Octamer tied together by H1
DNA methylation
Which Nucleotides
When in cell cycle?
Function
What organisms
C and A
Template strand is methylated during DNA replication which allows mismatch repair enzymes to distinguish between old and new strands<...
What does Histone Methylation do?
Inactivates DNA
What does Histone Acetylation do?
Relaxes DNA coiling allowing for transcription
Purines
Names
Rings
What is it made from?
“PURe As Gold”
Adenine, Guanine
2 rings
Glycine, Aspartate, Glutamine
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| Term | Definition |
|---|---|
Tuberous Sclerosis What kind of inheritance? Manifestations? | Autosomal Dominant w/ incomplete penetrance Harmatomas of CNS and Retina, Adenoma Sebaceum (cutaneous angiofibroma), Mitral Reg, Ash-Leaf Spots on skin, Cardiac Rhabdomyomas, Mental Retardation, Renal Angiomyolipomas and Renal Cysts, Seizures, Increased incidence of astrocytomas |
Histones? Charge Amino Acids What do they form? What ties it together? | Positively charged Lysine and Arginine Octamer tied together by H1 |
DNA methylation Which Nucleotides When in cell cycle? Function What organisms | C and A Template strand is methylated during DNA replication which allows mismatch repair enzymes to distinguish between old and new strands Prokaryotes |
What does Histone Methylation do? | Inactivates DNA |
What does Histone Acetylation do? | Relaxes DNA coiling allowing for transcription |
Purines Names Rings What is it made from? | “PURe As Gold” Adenine, Guanine Glycine, Aspartate, Glutamine |
Pyrimidines Names | “CUT the PY” Cytosine, Uracil, Thymine |
Molecular group on Guanine | Ketone |
Molecular group on Thymine | MeTHYl |
How is Uracil made? | Cytosine gets Deaminated |
RNA Nucleotides? | G-C, A-U |
DNA Nucleotides | G-C, A-T |
Which nucleotide bond is strongest | G-C has 3 hydrogen bonds |
How is DNA melting point affected | ↑ GC content –> ↑ melting temperature |
Nucleoside | Base + Ribose |
Nucleotide | Base + Ribose + Phosphate linked by 3’5’ phosphodiester bond |
What makes up Pyrimidines | Aspartate and Carbamoyl Phosphate |
Basic schematic of de novo purine synthesis | Start with sugar + phosphate (PRPP) Then add base |
Basic schematic of de novo pyrimidine synthesis | Make temporary base (orotic acid) Add sugar + phosphate (PRPP) Modify base |
Purine synthesis pathway | Ribose 5-P –> PRPP ->->-> IMP –> AMP and GMP |
Inhibition of de novo purine synthesis | 6-mercaptopurine blocks de novo purine synthesis |
Production of deoxyribonucleotides | Ribonucleotide reductase converts ribonucleotides into deoxyribonucleotides |
CTP synthesis | Ribose 5-P –> PRPP PRPP + Orotic Acid –> UMP –> UDP –> CTP |
dTMP synthesis | Ribose 5-P –> PRPP PRPP + Orotic Acid –> UMP –> UDP –> [Ribonucleotide reductase] –> dUDP –> dUMP –> [Thymidylate Synthase] –> dTMP |
What pathways is Carbamoyl Phosphate involved with? | de novo pyrimidine synthesis and urea cycle |
Ornithine transcarbamoylase deficiency What is it? Findings | OTC is a key enzyme in the urea cycle Deficiency leads to accumulation of carbamoyl phosphate which is then converted into orotic acid ↑ Orotic acid with hyperammonemia |
What inhibits Ribonucleotide reductase | Hydroxy Urea |
What inhibits Thymidylate Synthase? | 5-Fluorouracil |
What inhibits human Dihydrofolate reductase | Net result? | Methotrexate | ↓ dTMP |
What inhibits bacterial Dihydrofolate reductase | Net result? | Trimethoprim | ↓ dTMP |
THF and dTMP synthesis | THF --> N5N10 methylene THF --> [Thymidylate Synthase] --> DHF --> [Dihydrofolate reductase] --> THF |
Orotic Aciduria What is it? Pathway involved? Where is the defect? Genetics Findings Treatment | Inability to convert orotic acid to UMP de novo pyrimidine synthesis pathway UMP synthase Autosomal Recessive ↑ orotic acid in urine, Megaloblastic anemia (does not improve with B12 or folic acid), Failure to thrive, No hyperammonemia Oral uridine administration |
Adenine salvage pathway | Adenine + PRPP --> [APRT] --> AMP | AMP can become Nucleic acids, Adenosine, or IMP |
Fate of Adenosine in salvage pathway | Adenosine can become AMP or Adenosine deaminase (ADA) can turn it into Inosine |
Fate of IMP in purine salvage pathway | Hypoxanthine + PRPP --> [HGPRT] --> IMP | IMP can become inosine, AMP, or GMP |
Fate of Inosine in Purine salvage pathway | Adenosine --> Inosine | Inosine --> Hypoxanthine |
Fate of Hypoxanthine in Purine salvage pathway | Hypoxanthine can become IMP, Inosine, or Xanthine |
Fate of Guanine in Purine salvage pathway | Guanine +PRPP --> [HGPRT] --> GMP Guanine --> Guanosine Guanine --> Xanthine |
Fate of Guanosine in Purine salvage pathway | GMP --> Guanosine | Guanine ↔ Guanosine |
Fate of GMP in Purine salvage pathway | GMP can be come Nucleic Acids, IMP or Guanosine |
Adenosine Deaminase Deficiency PathoPhys Genetics What does it lead to Treatment | Excess ATP and dATP leads to an imbalance in nucleotide pool via feedback inhibition of ribonucleotide reductase thus preventing DNA synthesis thus ↓ Lymphocyte count Autosomal recessive SCID 1st disease to be treated by experimental human gene therapy |
Lesch-Nyhan Syndrome Deficiency Metabolic result Genetics Findings | "He's Got Purine Recovery Trouble" HGPRT mutation which converts hypxanthine into IMP and Guanine into GMP Excessive uric acid production and de novo purine synthesis X linked recessive Retardation, Self-Mutilation, Aggression, Hyperuricemia, Gout, Choreoathetosis |
Genetic Code Features Unambiguous Degenerate Commaless Universal | Each codon = 1 AA Most AA are coded by multiple codons except for Methionine (AUG) and Tryptophan (UGG) Nonoverlapping: fixed starting point at a continuous sequence of bases except in some viruses Conserved throughout evolution except in human mitochondria |
Silent mutation | Same AA usually at 3rd position of condon (tRNA wobble) |
Missense mutation | Changed AA to a similar AA |
Nonsense mutation | Early stop codon |
Frameshift | Misreading of all downstream nucleotides resulting in truncated, nonfunctional protein |
DNA topoisomerases Function What inhibits it | Creates a nick in the helix to relieve supercoil created during replication Fluoroquinolones inhibit prokaryotic topoisomerase II |
DNA pol III What organisms? Direction of synthesis Other functions? | Prokaryotic only 5' --> 3' Proofreads 3' to 5' |
DNA pol I What organisms Function Functions with directions | Prokaryotic only Degrades RNA primer and replaces it with DNA Synthesis 5' --> 3' Proofreading 3' --> 5' Exonuclease 5' --> 3' |
DNA ligase | Catalyzes the formation of phosphodiesterase bonds within strand of dsDNA. Joins Okazaki fragments |
Telomerase | Adds DNA to 3' end of chromosome to avoid loss of genetic material with every duplication |
Nucleotide Excision repair Process What kind of lesions does it repair Disease involving this pathway | Specific endonucleases release the oligonucleotide-containing damaged bases. Then DNA pol and Ligase fill and reseal the gap Repairs bulky helix distorting lesions Xeroderma pigmentosum: Prevents repair of pyrimidine dimers because of UV light |
Base Excision repair Process What kind of lesions does it repair? | Specific glycosylases recognize and remove damaged bases. Apurinic/Apyrimidinic endonucleases cut DNA at both sites. Empty sugar is removed. Gap is filled in and resealed Important in reapir of spontaneous/toxic deamination |
Mismatch Repair Process Disease | Newly synthesized strand is recognized, mismatched nucleotides are removed and gap is filled and resealed Mutated in Hereditary NonPolyposis Colorectal Cancer (HNPCC) |
Nonhomologous end joining Process Requirements Disease | Brings together 2 ends of DNA fragments to repair double stranded breaks No requirement for homology Mutated in ataxia telangiectasia |
Direction of DNA and RNA synthesis? | Energy source? | 5' --> 3' | 5' end of dNTP |
In which direction is mRNA read? | 5' --> 3' |
Direction of Protein Synthesis | N to C |
Most abundant type of RNA | rRNA |
Ways to remember types of RNA? | "Rampant, Massive, Tiny" |
Eukaryotic start codon | "AUG inAUGurates protein synthesis" | AUG (rarely GUG) which codes for Methionine |
Prokaryotic start codon | AUG which codes for formylmethionine |
mRNA stop codons | UGA: U Go Away UAA: U Are Away UAG: U Are Gone |
Promoter code | TATA Box | TATAAT and CAAT |
Start of transcription numbering | +1 |
Termination signal | AATAAA |
Eukaryotic RNA pol I, II, III Functions | Numbered in order that they are used in protein synthesis I: rRNA II: mRNA - can open DNA at promoter site III: tRNA No proofreading function but can initate chains |
Prokaryotic RNA pol | 1 RNA pol (multisubunit complex) makes all 3 kinds of RNA |
What inhibits RNA pol II | What does it lead to | α-amanitin (from mushroom) | Hepatotoxicity if ingested |
RNA processing in eukaryotes What is initial transcript called? What is it called if destined for transcription? Where does processing occur? | Heterogenous nuclear RNA pre-mRNA Processing occurs in the nucleus |
RNA processing in eukaryotes | Capping on 5' end with 7-methylguanosine Polyadenylation an 3' end Splicing out of introns |
What is required for RNA to be transported out of the nucleus | Only processed RNA can be transported out of the nucleus |
Polyadenylation What enzyme does it? Template? Signal | Poly-A polymerase Does not require a template AAUAAA |
Steps of Splicing pre-mRNA | Primary transcript combines with snRNPs (small nuclear ribonucleoproteins) and other proteins to form a spliceosome Lariat shaped (looped) intermediate is generated Lariat is released to remove intron precisely and join 2 exons |
Disease involving snRNPs | Lupus: autoAbs to spliceosomal snRNPs |
tRNA Length Secondary structure What is on end? Which end binds AAs | 75-90 NTs Cloverleaf form On 3' end is 5' CCA 3' along with a high percentage of chemically modified bases 3' is bound to AA |
tRNA Charging Enzyme Proofreading Energy | Aminoacyl-tRNA synthetase Scrutinizes AA before and after it binds tRNA If incorrect, bond is hydrolyzed AA-tRNA bond has energy for formation of peptide bond |
Tetracyclines | Bind 30S subunit and prevents attachment of aminoacyl tRNA to A site |
Eukaryote Ribosomes | Even #s | 40S and 60S |
PrOkaryote Ribosomes | Odd #s | 30S and 50S |
Protein synthesis initiation | Activated by GTP hydrolysis | Initiation Factors help assemble 40S ribsomal subunit with the initiator tRNA and are then released |
Protein synthesis Elongation | "Going APE" Aminoacyl-tRNA binds A site (except initiator methionine) rRNA catalyzes peptide bond formation transferring polypeptide into A site Peptidyl tRNA moved into P site and empty tRNA moves to E site |
Protein synthesis Termination | Stop codon recognized by release factors and complete protein is released from ribosome |
Aminoglycosides | Bind 30S and inhibit formation of initiation complex and cause misreading of mRNA |
Chloramphenicol | Binds 50S and inhibits peptidyl transferase |
Macrolides | Bind 50S and prevent release of uncharged tRNA after it has donated its AA |
Process of Proteasomal degradation | Attachment of Ubiquitin tags them for breakdown |
Stages of cell cycle | G1 --> [Rb, p53] --> S --> G2 --> Mitosis |
Interphase | G1, S, and G2 |
Stages of mitosis | Prophase, Metaphase, Anaphase, Telophase |
Regulation of Cell Cycle CDKs Cylcins Cyclin-CDK complexes | CDKs are constitutively present and inactive Cyclins are regulatory and are produced in a phase specific manner Cyclin-CKD complexes activate and the inactivate for cell cycle to progress |
Tumor Suppressors Names Function | p53 and Hypophosphorylated Rb | Normally inhibit G1 to S progression |
Permanent cell type Phase What do they form Examples | Remain in G0 Regenerate from stem cells Neurons, Skeletal muscle, Cardiac muscle, RBCs |
Stable cell types Name Phase Examples | Quiescent Enter G1 from G0 when stimulated Hepatocytes and Lymphocytes |
Labile cells Phase Examples | Never go to G0. Divide rapidly with a short G1 | Bone marrow, Gut epithelium, Skin, Hair follicles, Germ cells |
Rough Endoplasmic Reticulum What kind of proteins are synthesized here? Protein modifications | Site of synthesis of secretory (exported) proteins | N linked oligosaccharide addition to many proteins |
Nissl Bodies | RER in neurons Synthesizes ChAT (choline acetyltransferase) to make ACh and peptide NTs |
What do free ribosomes produce | Cytosolic and organellar proteins |
Which kind of cells are rich in RER? | Mucus-secreting goblet cells of SI and Ab secreting plasma cells |