1
Q
What is the rate limiting step in Pyrimidine synthesis?
A
Carbomoyl Phosphate 2
- cytosolic
2
Q
What is the rate limiting step in purine synthesis?
A
Phosphoribosyl Pyrophosphate synthetase (PRPP synthetase)
3
Q
What are the sources of carbons in the formation of purines?
A
CO2 Glycine Glutamine - provide Nitrogen Aspartate - provide nitrogen THF
4
Q
What are the sources of carbon for Pyrimidine Synthesis?
A
- Aspartate
- CO2
- Glutamine = provides nitrogen (carbamoyl phosphate)
5
Q
What inhibits ribonucleotide reductase?
A
Hydroxyurea
6
Q
What inhibits dihydrofolate reductase?
A
Trimethoprim = bacteria Methotrexate = humans
7
Q
What inhibits thymidylate synthase?
A
- 5-flourouracil
8
Q
Inhibits IMP dehydrogenase?
A
Mycophenolate
9
Q
Inhibits PRPP amidotransferase
A
- 6-mercaptopurine
10
Q
Features of Orotic Aciduria
A
- Orotic acid in urine
- no elevation in ammonia
- failure to thrive
- megaloblastic anemia uncorrected by B12 or folate
- autosomal recessive
- due to deficiency in orodylate synthetase and OMP decarboxylase
Treatment = supplement dietary uridine
11
Q
What accounts for positive charge in histones? Negative charge in DNA?
A
- Positive charge in histones = lysine and arginine
- Negative charge in DNA = phosphate
12
Q
Topoisomerase Inhibitors
A
Fluoroquniolones = inhibit prokaryotic topoisomerase 2 (DNA grade and topo 4)
Etoposides = inhibit eukaryotic topoisomerase
AntiScl70 = antibody to topoisomerase in diffuse scleroderma
13
Q
DNA polymerase differences in Prokaryotes vs. Eukaryotes
A
Prokaryotes
- DNA Poly 3 = builds both leading and and lagging strand
- DNA poly 1 = degrades RNA primer and replaces it with DNA
- have primase because it can’t make its own primer
- primosome = DNA helicase and primase (makes RNA primer)
Eukaryotes
- DNA polymerase alpha - makes own primer, and builds Okazaki fragments on lagging strand
- DNA polymerase delta = builds the leading strand
- DNA polymerase beta = DNA repair
- DNA polymerase gamma = replicates mitochondrial DNA
- telomerase is only found in eukaryotes and adds DNA to3’ ends to avoid loss of genetic material
14
Q
Missense mutation
A
- occurs with sickle cell anemia = glutamic acid to valine
15
Q
DNA repair
A
Single strand
- mismatch repair ==> HNPCC = increases risk of colon cancer
- nucleotide excision repair - for bulky damage ==> Xeroderma pigmentosum, Bloom syndrome (mutation of helicase)
- base excision repair - non bulky damage, removes altered base ==>
Double Strand
- Non-homologous end joining ==> ataxia telangiectasia, Fanconi anemia
- dsDNA repair = BRCA1 and BRCA2 mutations
16
Q
DNA and RNA differences
A
- OH’ at 2’ position of ribose for RNA not in DNA
- total purines = total pyrimidines
- DNA and histone synthesis occurs during S phase
17
Q
What is the difference between a 10nm and 30nm Chromatin
A
- there is no presence of H1 linker DNA in the 10nm
DNA –> 10nm chromatin –> 30nm chromatin –> 30nm with scaffolding proteins ==> Euchromatin —> high order packaging (HETEROCHROMATIN)
18
Q
DNA methylation
A
Template strand cytosine and adenine are methylated in DNA replication. Help to distinguish between old and new strands in prokaryotes. DNA methylation at CpG islands repress transcription.
19
Q
Histone Methylation vs. Acetylation
A
Methylation = represses DNA transcription Acetylation= relaxes DNA coiling and allows for transcription
20
Q
Nucleotides
A
- deamination of cytosine makes uracil
- the more G-C bonds you have the higher the melting temp of DNA
- phosphates are linked from 3’ to 5’ on the ribose sugars
21
Q
PNP deficiency
A
Severe deficit of T-cells
22
Q
Adenosine Deaminase Deficiency
A
- will have excess ATP and dATP which causes feedback inhibition of ribonucleotide reductase
- autosomal recessive
- will cause SCID = defiance of both T and B cells = causes severe recurrent infections, chronic diarrhea, failure to thrive, no thymic shadow on CXR of newborn
23
Q
Lesch Nyhan Syndrome
A
- defect in purine salvage pathway
- due to absent HGPRT
- causes excess uric acid production and de novo purine synthesis
- intellectual disability, self mutilation, gout, hyperuricemia, aggression, dystonia
Treatment = allopurinol and febuxostat
24
Q
Genetic Code features
A
- unambiguous = each codon specifies only 1 amino acid
Degenerate/redundant = most amino acids are coded by multiple codons (except methionine and tryptophan = AUG and UGG)
Commaless, no overlapping = read from a fixed starting point as continuous except in viruses
Universal = genetic code is conserved throughout human population except in humans mitochondria
25
Point Mutations
```
Transition = purine to purine or Pyrimidine to Pyrimidine
Transversion = purine to Pyrimidine
```
26
Frame shift mutation
Duchenne muscular dystrophy
27
Nucleotide Excision Repair
1. Endonucleases release the damaged bases on same strand
2. DNA polymerase and ligase fill and reveal the gap
Occurs in G1 phase of cell cycle
28
Base Excision Repair
1. Glycolyase removes damaged base and creates AP site (no purine or Pyrimidine site)
2. AP endoculease removes one or more nucleotides which cleaves the 5' end and lease cleaves the 3' end
3. DNA polymerase beta fills gap
4. DNA ligase seals it
Occurs though out cell cycle
- important in repair of spontaneous/toxic deamination
29
Mismatch Repair
- Newly Syntheisized strand is recognized
- mismatched nulceotides are removed, gap is filled and revealed
Occurs in G2 phase of cell cycle
Defective in HNPCC
30
NoN homologous End joining
Brings together 2 ends of DNA fragments to repair double stranded breaks.
- No requirement for homologous
- some DNA may be lost
Seen in Ataxia Talengiectasia, Fanconi Anemia
31
OPeron
Structural genes that are transcribed + promotors region + all regulatory regions
32
Transcription Factors
Need to be bound to promoter region to allow for transcription.
(Promoter regions = CCAT box, TATA box, Pribnow box TATAT)
33
Response Elements
Enhancer or repressor region
- can increase or decrease the rate of transcription
- location can be anywhere
34
Operator region
- found upstream
- can bind a repressor or inducer
Located between the promoter and regulatory gene
35
Structural Motifs
Help proteins bind to the DNA
- helix loop helix
- helix turn helix
- zinc finger motif = has zinc on it
- Leucine Zipper protein = has a lot of leucine residues
36
Lac Operon
- helps with digesting lactose with Beta-galactosidase
- the Operon regulates transcription of enzyme
CAP = transcription factor => needed for transcription to take plans--> only around when glucose is absent
Repressor protein is always bound to Operon unless lactose is present
37
Eukaryotes RNA Polymerases
RNA poly 1 => rRNA (made in nucleolus And most numerous)
RNA poly 2 =-> mRNA (made in nucleus and largest RNA )
RNA poly 3 ==> tRNA (made in nucleus and tiniest)
38
Alpha-amanitin
Mushroom toxin that inhibits RNA Poly 2
| - can cause hepatotoxicitiy and liver failure
39
Prokaryotic RNA Polymerases
- have one RNA polymerase that makes all 3 RNA
| - Rifampin inhibits this ==> causes red secretions, and revs up CYP450
40
Transcription Termination in Prokaryotes
- Rho factor an RNA dependent ATPase
- Rho independent - region of DNA rich with Guanine and Cytosine causing a hair pin loop that puts tension on RNA polymerase and pressure on Uracil rich part of RNA and removes the complex.
41
Actinomycin D
Inhibits transcription in both eukaryotes and prokaryotes
42
TRNA
- aminoacyl tRNA synthetase uses ATP to put amino acid on the 3' end (hydroxyl end that ends with CCA) of the tRNA
43
Ribosomes
```
Eukaryotes = 60S & 40S --> 80S
Prokaryotes = 50S and 30S --> 70S
```
44
Translation
Initiation
- initiation factors (IF2) help to put the small subunit to the tRNA at P site with methionine and then brings the large subunit. (Overall initiation factors help to put the subunits together)
Elongation
- elongation factors help the incoming tRNA to bind to the A site and uses GTP for energy
- peptidyltransferases (found in 23S rRNA in prokaryotes) transfers the amino acid in the P site to the amino acid in the A site
Translocation
- moves tRNA from P site to E site and moves elongating amino acids
- requires Elongation Factor G in prokaryotes
- requires Elongation factor 2 in eukaryotes (diptheria toxin and Exotoxin A from pseudomonas inhibits)
Termination
- At stop codon the release factor comes in and releases everything
For antibiotic inhibition
Buy AT 30 CCELL at 50
30S = aminoglycoside and tetracyclines
50S = Clindamycin, Chloramphenicol, Erythromycin(macrolides), Linezolid, and Lindamycin
45
Amino glycosides
Bind to 30S subunit before initiation so protein synthesis is inhibited
46
Linezolid
- also inhibits initiation of translation
| - binds to 50S subunit
47
Tetracyclines
Bind to 30S subunit and prevents tRNA from getting into A-site
48
Chloramphenicol
Inhibits peptidyltransferase of 23S rRNA to inhibit elongation of the amino acid
49
Macrolides
Inhibits translocation step of protein synthesis
50
Clindamycin and Lincomycin and Streptogramins
- binds to 50S subunit and blocks translocation
51
RER vs Free Ribosomes
RER proteins
- secreted proteins
- membrane bound proteins
- lysosomal enzymes
Free ribosomal proteins
- cytoplasmic proteins
- mitochondrial proteins
- proteins for peroxisosomes
SRP = protein that directs free ribosomes to RER
- if absent proteins accumulate in cytosol
52
N-terminal hydrophobic signal sequence
- required on proteins that are destined to be secreted outside of cell, embedded in cell membrane, or directed to lysosomes
- for RER proteins.
53
I cell disease (inclusion cell disease)
defect in N-acetylglucosaminyl-1phosphotransferase
- failure of Golgi to phosphorylate mannose residues on glycoproteins
- instead proteins are secreted extracellularly rather than delivered to lysosomes
- causes coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes
- fatal in childhood
54
Peroxisome
membrane enclosed organelle
- that is involved in the catabolism of very-long chain fatty acids, branched chain fatty acids, and amino acids
- bile acid synthesis
- synthesis and degradation of peroxide (contains catalase)
55
Microtubules
```
Dynein = retrograde transport
Kinesin = anterograde transport
Cilia = 9+2 arrangement of microtubules
```
Drugs that act on microtubules
- Mebendazole/thiabendazole ==> parasites
- Griseofulvin ==> antifungal
- Vincristine/Vinblastine
- Paclitaxel ==> antineoplastic for breast cancer
- Colchicine =-> antigout
56
Chediak Higashi Syndrome
- autosomal recessive
- microtubule polymerization defect ---> impaired fusion of phagosomes and lysosomes
Symptoms
- neutropenia
- recurrent pyogenic infections
- partial albinism
- peripheral neuropathy
57
Ouabain
inhibits Na/K+ pump by binding to K+ site
58
Types of Collagen
Type 1 = Bone, Skin, Tendon, dentin, fascia, cornea, late wound repair
Type 2 = Cartilage, vitreous humor, nucleus pulpous
Type 3 = Reticulin - skin, blood vessels, uterus, fetal tissue, granulation tissue
Type 4 = basement membrane, basal lamina, lens
59
Collagen Synthesis and Structure
Inside Fibroblasts
RER
1. Synthesis of pre pro alpha chain with N-terminal signal sequence, primary structure made of tripeptide Gly-X-Y
2. Removal of signal sequence by signal peptidase to form pro alpha chain
3. Hydroxylation of selected prolines and lysine using Vitamin C --> Scurvy with vitamin C deficiency
4. Glycosylation of selected hydroxylysines and formation of triple helix (pro collagen) --> Osteogenesis imperfecta (problems forming triple helix
5. Exocytosis of pro collagen into extracellular space
Outside Fibroblasts
6. Cleavage of disulfide rich regions of pro collagen transforming it into tropocollagen
7. Cross linking: assembly into fibrils stabilized by lysyl hydroxidase (requires oxygen and copper) --> problems with cross linking = Ehler Danlos and Menkes disease
60
Euler Danlos Syndrome
Mutation in collagen genes and lysyl hydroxylase gene
- hyperetensible skin
- bleeding and easy bruising
- hypermobile joints, dislocations
- varicose veins
- ecchymoses, arterial and intestinal ruptures
Joint and Skin Symptoms = Classical type = mutation in collagen type 4
Vascular type = deficient type 3 collagen
61
Menkes Disease
X-linked recessive
- impaired copper absorption and transport due to defective menkes protein (ATP7A)
- leads to decreased activity of lysyl oxidase and decreased cross linking
Symptoms
- brittle, kinky hair, growth retardation, hypotonia
- arterial tortuosity and rupture
- cerebral degeneration
- osteoporosis, anemia
62
Marfan Syndrome
defect in fibrillar, a glycoprotein that forms a sheath around elastin
63
PCR
used for paternity testing and HIV testing to amplify microsatelite repeats
- Denaturation
- annealing
Elongation
64
Karyotyping
- metaphase chromosomes are stained, ordered and numbered according to morphology size
- used to diagnose chromosomal imbalances = trisomies and sex chromosome disorders
65
FISH
- used to detect if a particular gene is present or not
| - for micro deletions
66
Incomplete Penetrance
Not all individuals with a mutant genotype show the mutant phenotype
67
Variable Expression
phenotype severity varies among individuals with same genotype
68
Locus heterogeneity
Different genes cause the same phenotypic expression
| example: Osteogenesis imperfecta
69
Mosaicsim
cells in body have different genes
presence of genetically distinct cells in the same individual
ex: McCune Albright syndrome
70
Pleiotropy
One gene contributes to multiple phenotypic effects
71
Autosomal Dominant Diseases
```
Familial hypercholesterolemia
Huntington's Disease = 4
MEN Syndromes
Hereditary spherocytosis
Autosomal dominant polycystic kidney disease = 16
Familial adenomatous polyposis = 5
Hereditary hemorrhagic telangiectasia/Osler Weber Rendu Syndrome
Marfan syndrome = 15
NF1 and NF2 = 17, 22
Tuberous Sclerosis
VHL disease = 3
```
72
Autosomal Recessive Diseases
-often due to enzyme deficiency
```
Glycogen Storage Diseases
PKU
Thalasemias
Sickle Cell Disease
Cystic Fibrosis
Hemochromatosis
Kartegener Syndrome
Mucopolysaccharidoses (except Hunter)
Sphingolipidoses (except Fabry)
Wilsons Disease
Classical Galactosemia
```
73
X-linked Recessive
```
G6PD deficiency
Duchenne Muscular dystrophy and Becker
Lesch Nyhan Syndrome
Hemophilia A and B
Fabry
Hunter
Ocular albinism
Ornithine transcarbamylase deficiency
Bruton Agammaglobulinemia
Wiskott Aldrich Syndrome
```
74
X-Linked Dominant
Fragile X Syndrome
Rett Syndrome
Hypophophatemic rickets
Charcot Marie Tooth Syndrome
75
Dominant negative mutation
Exerts dominant effect
| A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
76
McCune Albright Syndrome
```
mutation affecting G-protein signaling
- unilateral Cafe-au last spots
-polyostotic fibrous dysplasia
precocious puberty
multiple endocrine abnormalities
Lethal if mutation occurs before fertilization
```
77
Uniparental Disomy
offspring receives 2 copies of a chormomse from 1 parent and no copies from the other
Heterodisomy = meiosis 1 error
Isodisomy = meiosis 2 error
78
Hardy Weinberg
Be careful for autosomal dominant disease. 2pq is not carrier state
for X-linked recessive disease
male = q
females = q2
79
Acrocentric chromosomes
13-15
21-22
have very tiny p arms
80
Aneuploidy
all autosomal monosomes are incompatible with life
all trisomies are incompatible with life except 13, 18, 21 ==> due to non disjunction during meiosis 1 or 2
81
Robertsonian Translocation
more common than reciprocal translocations
- occur only in acrocentric chromosomes 13-15 and 21-22
- causes loss of short p arms and fusion of long q arms of chromosomes
-
82
Trinucleotide Repeat Expansion Diseases
Fragile X = CGG
Frierich Ataxia = GAA
Huntington's = CAG
Myotonic dystrophy = CTG
83
Fragile X syndrome
defect affecting the methylation and expression of the FMR1 gene
- 2nd most common cause of mental retardation other than down syndrome
- post-pubertal macroorchidism (enlarged testes)
- long face with a large jaw
- large everted ears
- autism
- mitral valve prolapse
TRI REPEAT: CGG
84
Mitochondrial Inheritance
Leber Hereditary optic neuropathy
85
Type 1 vs. Type 2 muscle fibers
Type 1 (slow twitch = red)
- low level sustained force = postural maintenance
- aerobic metabolism gets ATP
- high myoglobin and mitochondrial concentration
- paraspinal and soleus muscles = postural skeletal muscles
Type 2 (fast twitch) = white
- rapid forceful pulses of movement
- ATP energy from anaerobic glycogenolysis and glycolysis
- Lats, Pec, Biceps, Deltoid
86
Macula
- yellow spot located near the center of the retina
- made of densely packed cones
- each macular cone synapses to a single bipolar cell which in turn synapses to a single ganglion cell
- the visual acuity in the macula and fovea are greatest than any other area of the retina
Macular lesions impair central vision and cause central scotomata
- macular degeneration = most common cause of blindness in old people = progressive loss of central vision due to deposition of fatty tissue (drusen) behind the retina (dry MD) and neovascularization of the retina (wet MD)
A scotoma = visual defect that occurs due to a pathological process that involves parts of the retina or optic nerve resulting in a discrete area of altered vision surrounded by zone of normal vision. Lesions of the macula cause central scotomas.
87
Thalamus relay centers
Ventral posterior lateral nucleus = input from spinothalamic tract and dorsal columns
Ventral posterior medial nucleus = input from the trigeminal pathway
Damage to these nuclei result in complete contra lateral sensory loss
88
Lacunar Infarcts (lacunes)
Infarcts from occlusion of the small penetrating arteries that supply the deep brain structures of the basal ganglia (lenticulostriate arteries)
- infarcts can come from hypertension or diabetes mellitus
- lipohyalinosis and microatheromas are main causes of lacunar infarcts
Lipahyalinosis = occurs due to leakage of plasma proteins through damaged endothelium and is characterized by hyaline thickening of the vascular wall, collagenous sclerosis, and accumulation of mural foamy macrophages ==> causes 5-6mm cavities in the deep structures of the brain with clear fluid
Microatheromas= atheresclerotic accumulation of lipid laden macrophages with the intimal layer of a penetrating artery near its origins of the parent vessel.
89
Sickle Cell anemia
- causes acute chest syndrome, abdominal pain, and bone pain due to vaso-occlusive events in the lungs, spleen and bone
- Exertional dyspnea, pneumonia resulting life threatening acute chest syndrome
Due to point mutation that causes valine to substitute for glutamic acid in the 6th position of the beta globin chain of hemoglobin
90
Parotitis
Acute bacterial infection of the parotid gland
- usually due to S. Aureus or anaerobes
- risk factors: dehydration, intubation, medications that decrease salivary flow, salivary flow obstruction, intense teeth cleaning
Clinical presentation
- Trismus, dysphagia, fevers chills
Diagnosis
- parotid duct inflammation, obstruction by a stone, or abscess on CT or ultrasound
- Elevated serum amylase, normal lipase, and no evidence of pancreatitis
91
Protein Electrophesis
- separated based on size and charge
| - well is in the middle
92
Down Syndrome
Trisomy 21
- mental retardation
- flat facies
- prominent epicanthal folds
- gap between 1st 2 toes
- duodenal atresia
- hirchsprungs disease
- congenital heart disease (ASD)
- early onset Alzheimer's because amyloid protein is on Chromsome 21
- increased risk of ALL and AML
Most cases are due to meiosis nondisjunction
First trimester ultrasound = increased unchallenged translucency and hypoplastic nasal bone, serum PAPP-A is decreased and free HCG is increased
Second trimester ultrasound = decreased alpha fetoprotein, increased B-HCG, decreased estriol, increased inhibin A
93
Edwards Syndrome
Trisomy 18
- severe intellectual disability
- rocker bottom feet
- micrognathia (small jaw)
- low set ears
- clenched hands with overlapping fingers
- prominent occiput
- congenital heart disease
- death usually occurs within 1 year of birth
2nd most common trisomy after Down syndrome
election age = 18
94
Patau Syndrome
Trisomy 13
- mental retardation
- rocker bottom feet
- micropthalmia
- microcephalic
- cleft lip/palate
- holoprosencephaly
- polydactyl
- congenital heart disease = VSD
- cutis a plasia
- Death usually occurs within 1 year of birth
Puberty = 13
95
Cri-du-chat Syndrome
Congenital micro deletion of short arm of Chromsome 5
- microcephaly
- moderate to severe intellectual disability
- high pitched crying/mewing
- epicanthal folds
- VSD
96
Williams Syndrome
Congenital micro deletion of long arm of chromosome 7
- elfin facies
- intellectual disability
- hypercalcemia = increased sensitivity to vitamin D
- well developed verbal skills
- extreme friendliness with strangers
- cardiovascular problems
97
Zinc Deficiency
Delayed wound healing
- hypogonadism
- decreased adult hair = axillary, facial, pubic
- decreased immune response
- infertility
- decreased taste = dysgenic
- anosmia
- acrodermatitis enteropathica = scaly plaques/rash
- predisposes to alcoholic cirrhosis
- growth retardation
- depressed mental function
- impaired night vision
98
Mercury Poisoning
Accumulates in brain and kidney ==> peripheral neuropathy
- acrodynia = peeling in the fingertips
- abdominal pain
Common sources: shark, swordfish, tilefish, mackerel, old thermometers, batteries
99
Lead Poisoning
Bluish colored lines on the gingivae and on metaphysics of long bone = burton's lines
- basophilic stippling in red blood cell = inhibits rRNA degradation = aggregates of rRNA
- mental deterioration in children
- headache, memory loss, demyelination = adults
Affects the GI and Kidney
Lead inhibits ferrochelatase and ALA dehdratase- decreases heme synthesis and increases RBC protoporphyrin
Wrist drop and foot drop
Treatment
Dimercaprol and EDTA = 1st line for Adults
Succumbed = chelation for kids
100
Enzyme terminology
```
Kinase = uses ATP to add high energy phosphate group on substrate
Phosphorylase = adds inorganic phosphate onto substrate without using ATP
Dehydrogenase = catalyzes oxidation-reduction reactions
Mutase = relocates a functional group within a molecule
```
101
Rate Determining Enzymes of metabolic processes
Look at page 96 in your STEP book
102
Dantrolene
Prevents release of Calcium from Sarcoplasmic reticulum
Used for malignant hyperthermia and neuroleptic malignant syndrome
103
RBC Metabolism
- has no mitochondria so can't do oxidative phosphorylation (ETC)
- only does glycolysis (anaerobic oxidation)
NO nucleus
104
Glycolysis Key Facts
Malate-aspartate shuttle = 32 ATP per glucose
-heart, kidney
Glycerol-3-phosphate shuttle = 30 ATP per glucose
- brain, skeletal muscle
105
Types of Glucose Transporters
Glut 1
- RBC's, endothelium of BBB, other tissues
- Basal glucose uptake in erythrocytes and Brain
GLUT 2 = removes excess glucose from thee blood
- liver
- Pancreatic Beta cells = regulates insulin secretion
Glut 3
- neurons
- placenta
Glut 4
- skeletal muscle and adipose tissue
- requires insulin
Glut 5
- fructose uptake in the GI tract
106
Pyruvate Kinase Deficiency
- hemolysis because RBC depend on glycolysis for ATP to maintain membranes with Na/K ATP pump
- will cause speculated RBC = burr cells
- increased 2,3 BPG = due to offloading of oxygen into tissues and improved exercise
107
De Vivo Disease
Glut 1 deficiency
- decreased glucose uptake in brain
- caused developmental defects, microcephaly, repeated seizures, ataxia,
Treatment = ketogenic diet = protein and high fat diet = Brain will use ketones as alternative energy source
108
Monogenic Diabetes (MODY)
Glucokinase deficiency
- autosomal dominant mutation
- increased blood glucose
- milder than type 1 diabetes
109
Pyruvate Dehydrogenase Complex
TLC 4 nobody
- T = Thiamine pyrophosphate = active form of thiamine
- L = Lipoic Acid
- C = Coenzyme A = from B5
- 4 = FAD = Vitamin B2
- Nobody = NAD = B3
Same thing applies to alpha ketoglutarate dehydrogenase
110
Arsenic Poisoning
Can inhibit Lipoic Acid and causes skin cancer
- Garlic Breath
- vomiting
- rice water stool
111
Private Dehydrogenase Deficiency
X-linked congenital defect
Acquired defect = from arsenic exposure that interferes with Lipoic acid or B-vitamin deficiency
Causes a buildup of pyre ate that gets shunted to lactate and alanine
- Treat: high fat diet and ketogenic amino acid (lysine and leucine), give deficient vitamin
112
Aminotransferases
- used to donate an amino group to alpha-ketoglutarate in order to create glutamate
- Named by the donor amino group
- Alanine Aminotransferase (ALT) ==> creates glutamate + pyruvate
- Asparate Aminotransferase (AST) ==> creates glutamate + oxaloacetate
113
What step in the TCA cycle creates GTP?
Succinyl CoA to Succinate
| By Succinate thiokinase/Succinyl-CoA synthetase
114
Bohr vs. Haldane Effect
Haldane Effect
- in the lungs the binding of oxygen to hemoglobin drives the release of H+ and CO2 from hemoglobin
Bohr Effect
- in peripheral tissues high concentrations of CO2 and H+ facilitate oxygen unloading from hemoglobin
115
How do spliceosomes remove introns?
Remove introns containing GU at the 5' splice site and AG at the 3' splice site
116
What happens to the oxygen dissociation curve if hemoglobin is separated into single alpha and beta subunits?
It will look like the myoglobin curve
- if separated the monomer if subunits will demonstrate a hyperbolic oxygen-dissociation curve similar to that of myoglobin
117
When does gluconeogenesis begin in the post-absorptive period? When does it become fully active?
Begins 4-6 hours after last meal
| Fully active when glycogen stores are depleted 10 to 18 hours after last meal
118
How does the pattern of fuel production and usage change in early starvation? 24 hours after last meal
Produce glucose and fatty acids
Brains uses mainly glucose
Muscles and other tissues use some glucose but mainly fatty acids
119
Intermediate Starvation (48 hours after last meal)
```
Glucose from glucogenesis
Fatty acids (adipose) and ketone bodies (liver)
```
Brain uses predominantly glucose but some ketone bodies
Muscles and other tissues use predominantly fatty acids but some ketone bodies
120
What metabolic scenario favors the synthesis of ketone bodies?
When production of acetyl CoA from oxidation of fatty acids exceeds the oxidative capacity of the TCA cycle due to excess gluconeogenesis occuring because of starvation
121
Prolonged Starvation (5 days after meal)
Glucose = from gluconeogenesis
Fatty acids from adipose tissue
Ketone bodies from liver
Brain uses predominantly ketone bodies
Muscles and other tissues are predominantly using fatty acids but also some ketone bodies and a little bit of glucose
122
Kwarshiorkor
Protein malnutrition
- Fatty liver disease = due to inability to make apolipoproteins so lipids accumulate in liver
- edema = due to decreased oncotic pressure
- anemia
- skin lesions
- de pigmentation of skin and hair = lack of protein
FLAME
Skinny child, muscle wasting, large abdomen from ascites
123
Marasmus
Total energy malnutrition = total calorie malnutrition
* muscle wasting
- subcutaneous fat loss
- edema
If person starts to eat again after marasmus for 5 days = refeeding syndrome
- cells pull nutrient from blood = drop in serum levels of magnesium, phosphate, and potassium
- can cause arrhythmias and neurological problems
- overall depletion of ATP because cells are phosphorylating things to keep it inside the cell
124
Apolipoproteins
Apo-A1 = activates LCAT to transfer cholesterol from tissues to HDL
CETP = is an enzyme that is needed to transfer cholesterol from LDL particles to HDL
Mediates uptake of remnant particles = Apo E
SR-B1 = Scavenger Receptor B1
- needed for uptake of HDL cholesterol into the liver
125
Abetalipoproteinemia
- autosomal recessive disorder
- decreased Apo-B48 and ApoB100
- enterocyte will have a hard releasing chylomicrons
- will cause decrease in chylomicrons and decrease in VLDL
Due to mutation in MTP gene needed for production of Apo-B48 and ApoB100
Clinical Presentation
- failure to thrive
- Steatorrhea
- impaired transport of ADEK
- enterocytes will be swollen with TAG's
- acanthocytosis = due to alteration in RBC membrane = spiked
- ataxia, night blindness = deficiency of Vitamin A
Treatment
- Vitamin E
126
Type 1 Hyperchylomicronemia
```
Autosomal recessive
- deficiency of LPL or ApoC2
- increased levels of chylomicrons, TAG's, cholesterol
Presentation
- Pancreatitis = due to hyperTAG build up
- hepatosplenomegaliy
- pruritic xanthomas
- creamy layer in super Natant
```
NO increased risk of atherosclerosis
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Type 2a Familial hypercholesterolemia
Autosomal Dominant
- absent or defective LDL receptors
- increased LDL and cholesterol in blood
Clinical Presentation
- Xanthomas (Achilles tendon) (histiocytes filled with lipids)
- corneal Arcus (lipid deposition in the cornea)
- Xanthelesma (lipid deposition on eyelid)
- increased risk of atherosclerosis at young age = accelerated
- double dominant mutation = MI in 20's
128
Type 4 Hypertriglyceridemia
Autosomal dominant
- Overproduction of VLDL from liver
- increased blood levels of VLDL and TG
Clinical Presentaiton
- increased TAG's can cause acute pancreatitis
129
Cholesterol Synthesis
- comes from Acetyl CoA
- HMG CoA reductase = rate limiting enzyme
- Statins inhibit
130
Fatty Acid Synthesis
Precursor
- Acetyl CoA
Location = cytoplasm of hepatocytes
Rate Limiting Enzyme = Acetyl CoA carboxylase
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Fatty Acid Degradation (Beta oxidation of fatty acid)
- Location = mitochondria
- Rate limiting Enzyme = Carnitine acyltransferase 1 (carnitine palmotyl transferase -1)
- deficiency of enzyme = accumulation of long chain fatty acid in the cytoplasm = weakness, hypotonia, hypoketotic acidemia.
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What does insulin do to lipoprotein lipase?
insulin increases the activity of LPL to allow fatty acid release from VLDL and Chylomicrons
133
What does the cardiac muscle use for energy?
Well fed = fatty acids
| Fasting = Fatty acids + ketones
134
What type of muscle fibers increase in trained athletes?
Slow twitch fibers and the number of mitochondria increases in trained athletes
135
Glucokinase vs. Hexokinase
Glucokinase
- located in the the liver and beta cells of pancreas
- high Km and high Vmax
- induced by insulin
- mutation = MODY = maturity onset diabetes of the young
Hexokinase
- other tissues
- low Km and low Vmax
- not induced by insulin
- inhibited by Glucose-6-phosphate
136
Hepatic Lipase
Converts IDL to LDL
137
Essential Amino Acids
```
Essential AA = PVT TIM HALL
Phenylalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histidine
Leucine
Lycine
```
All essential amino acids need to be supplied by diet.
- the Brush border can absorb di and tripeptides
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Basic AA
Lysine Arginine(most basic) Histidine
```
A&H = needed during periods of growth
A&L = nuclear localization signals and high in histones
```
Basic charge = + charge at body pH
Only histidine has no charge at body pH
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Acidic Amino Acids
Aspartate and Glutamate
| - negatively charged at body pH
140
Ornithine Transcarbamylase Deficiency (OTC)
- most common urea cycle disorder
- X-linked recessive
- can't use urea cycle
- evident within the first few days of life
- Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway)
Clinical presentation
- increased orotic acid in blood and urine
- decreased BUN (can't make urea)
- no megaloblastic anemia
- symptoms of hyperammonemia = tremor (asterixis ), slurring of speech, somnolence, vomiting, cerebral edema, blurred vision ==>elevated ammonia levels ==> hepato encephalopathy (liver disease can also cause this)
Treatment = low protein diet
- phenyl butyrate
- benzoate
- biotin = stimulates OTC
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N-acetylglutamate Synthase Deficiency
- required cofactor for carbamoyl phosphate synthetase 1
- absence of N-acetylglutamate ==> hyperammonemia
- Presents in neonate as poorly regulated respiration and body temperature, poor feeding, developmental delay, intellectual disability
=> same presentation as CPS1 deficiency
142
Alkaptonuria
Ochronosis
- congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate --> pigment forming homogenistic acid accumulates in tissue
- autosomal recessive and usually benign
Clinical Presentaiton
- dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air. May have debilitating athralgias (homogentistic acid toxic to cartilage)
143
Homocystinuria
- Deficiency of cystathionine Synthase = decrease methionine and increase cysteine, B12, folate, B6
- decreased affinity of the cystathionine synthase for B6
- homocysteine methyl transferase deficiency
Clinical manifestations
- mental retardation
- tall stature = marfinoid like habitus
- osteoporosis
- kyphosis
- atherosclerosis
- subluxation of the lens of eye downward (also occurs in Marfan syndrome = upward lens dislocation)
144
S-adenosyl-methionine
- transfers methyl unit in body = creates epinephrine and phosphocreatinine
145
Cystinuria
Hereditary defect of the renal PCT and intenstinal amino acid transporter that prevents the reabsorption cysteine, ornithine, lysine, and arginine (COAL)
Autosomal Recessive
Clinical presentation
- excess cystine in the urine leading to hexagonal cysteine stones
Prevention of stones = acetazolamide
146
Maple Syrup Urine Disease
Autosomal Recessive = I LoVe Maple Syrup
Blocked degradation of branched amino acids = Isoleucine, Leucine, Valine duel to deficiency of branched chain alpha ketoacid dehydrogenase complex
Increased alpha ketoacid said in the blood and urine especially those of leucine
Clinical Presentation
- CNS defects
- intellectual disability
- death
Urine smells like maple syrups or burnt sugar
147
DKA
In DKA the levels if 3-hydroxybutyrate increases 5x the increase in acetoacetate
148
Lysosomal Storage Disease
--All AR except Fabry and Hunter XR : so the Hunter is pointing his gun to the X target. Hurler who's like Hunter [is Mucopolysaccharidosis] but because of corneal clouding he can't hunt well. By the way both Hunter and Hurler accumulate Heparan sulfate [dermatan sulfate is easy to remember once you get the first]. All you need to really memorize then is Hurler is alfa iduronidase and you'll remember the other by exclusion.
--No man picks is nose with hi- Sphinger "Nieman Pick - Sphingomyelinase".
--Gaucher-Glucocerebrosidase-Glucocerebroside 3G "have u Got ur iPhone 3G!"
--Cherry-Red spot is a hyphenated term and so as Nieman-Pick and Tay-Sach.
--Ashkenazi Jews have Tay-Sachs Nieman-Pick and Gaucher common.
--Angiokeratoma is a Fabric of vessels and Galaxy of skin spots: which means that Angiokeratoma is seen in Fabry disease in which there's Galactosidase deficiency and epidermal keratosis.
--Krabbe's disease: just remeber Globoid Cells
--Metachromatic Leukodystrophy: ... well I don't know how to remember Aryl sulfatase
149
Amino Acids modified in the Golgi
- serine
- threonine
- asparagine
