Biochemistry Flashcards
Another name for a proteoglycan
Sugar backbone + protein
Mucopolysaccharide
A GAG consists of
Repeating disaccharide units of: acid sugar (glucuronic acid, iduronic acid) & amino sugar (glucosamine, galactosamine)
6 major groups of GAG include:
- CS #1 (cartilage, bone, heart valves)
- Hyaluronic acid (no sulfate, not covalently attached to proteins)
- KS
- DS
- Heparan Sulfate (negatively charged, acetylated glucosamine)
- Heparin (more sulfated than HS)
Cartilage consists of these GAGs (3)
CS, KS, hyaluronic acid
How is a GAG linked to a protein to form a proteoglycan?
Trihexoside linkage (gal-gal-xy) + serine
GAG’s are synthesized using what enzymes
Glycosyl transferases
Who is the sulfate donor when it comes to proteoglycan synthesis?
PAPS (with sulfrotransferase)
What is I cell disease?
Inability to transport hydrolytic enzymes to lysosomes 2/2 to inability to phosphorylate mannose
- Skeletal abnormalities, psychomotor, no joint movement
- Substances accumulate in lysosome; enzymes accumulate in plasma
O-glycosidic links in glycoproteins are made by…
OH- of serine/threonine
What are several examples of glycoproteins?
Cell surface receptors, blood group Ag, collagen, fibronectin
The pathogenesis of E. coli & H. pylori as it relates to glycoproteins
E. coli: mannose in plasma membrane
H. pylori: gastric epithelium
COPI vs COP2 cellular trafficking
What about clathrin?
COP1: retrograde: Golgi –> ER
COP2: anterograde: ER –> Golgi
Clathrin: Golgi –> Lysosomes; Plasma membrane –> Endosomes
What GAG can be injected into the joints of patients with osteoarthritis?
Hyaluronic acid
Fabry’s disease: deficient enzyme
Alpha-galactosidase
Gaucher’s disease: deficient enzyme
Glucocerebrosidase
Niemann-Pick disease: deficient enzyme
Sphingomyelinase
Tay-Sachs disease: deficient enzyme
Hexosaminidase A
Krabbe’s disease: deficient enzyme
Galactocerebrosidase
Metachromatic leukodystrophy: deficient enzyme
Aryl sulfatase
Hurler’s syndrome: deficient enzyme
Alpha-L-iduronidase
Hunter’s syndrome: deficient enzyme
Iduronate sulfatase
X-linked lysosomal storage disorders
Hunter’s, Fabry’s
Cherry-red spot macula lysosomal storage disorders
Tay-Sachs, Niemann-Pick (+HSM)
Corneal clouding lysosomal storage disorders
Hurler’s disease
Fabry’s disease: accumulated substrate
Ceramide trihexoside
Gaucher’s disease: accumulated substrate
Glucocerebroside
Niemann-Pick disease: accumulated substrate
Sphingomyelinase
Tay-Sachs disease: accumulated substrate
GM2 ganglioside
Krabbe’s disease: accumulated substrate
Galacrocerebroside
Metachromatic leukodystrophy: accumulated substrate
Cerebroside sulfate
Hunter’s disease & Hurler’s disease: accumulated substrate
Heparan and dermatan sulfate
Lysosomal storage disorder: peripheral neuropathy of hands/feet, angiokeratomas, CV/renal disease
Fabry’s disease
Lysosomal storage disorder: most common; HSM, aseptic necrosis femur, bone crises, macrophages that look like crumped tissue paper
Gaucher’s disease
Lysosomal storage disorder: Progressive neurodegeneration, HSM, cherry-red spot macula, foam cells
Niemann-Pick disease
Lysosomal storage disorder: progressive neurodegeneration, developmental delay, cherry-red spot macula, onion-skin lysosomes, no HSM
Tay-Sachs disease
Lysosomal storage disorder: peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Krabbe’s disease
Lysosomal storage disorder: Central and peripheral demyelination with ataxia, dementia
Metachromatic leukodystrophy
Lysosomal storage disorder: developmental delay, gargoylism, airway obstruction, corneal clouding, HSM
Hurler’s syndrome
Lysosomal storage disorder: Aggressive behavior, no corneal clouding
Hunter’s syndrome
Regulation of heme synthesis in the liver vs. RBC (bone marrow). Be sure to name the isoforms of the regulatory enzyme.
Liver (ALAS1): stops with increased heme and hemin
RBC (ALAS2): availability of intracellular Fe
Heme in the liver is used to synthesize…
Whereas heme in the RBC is coupled to the synthesis of globin.
Cytochrome p450
Lead poisoning affects these 2 enzymes.
What accumulates?
ALA dehydratase & Ferrochelatase
Accumulation: ALA & Protoporphyrin
Presenting symptoms of lead poisoning
Microcytic anemia; GI/renal disease
Children: mental deterioration (paint)
Adults: headache, memory loss, demyelination (battery, ammunition, radiator factory)
Environmental exposure in battery/ammunition/radiator factory
Lead
Acute intermittent porphyria affects this enzyme.
What accumulates?
Prophobilinogen deaminase or HMB synthase
Accumulation: Porphobilinogen, ALA, uroporphyrin (urine)
Presenting symptoms of acute intermittent porphyria
Painful abdomen, port wine colored urine, polyneuropathy, psychological disturbance, precipitated by dugs
Treatment of acute intermittent porphyria
Glucose, heme (inhibit ALAS)
Deficiency of ALAS results in…
Sideroblastic anemia (X-linked)
Sideroblastic anemia inheritance
X-linked
Enzyme deficiency in porphyria cutanea tarda
Uroporphyrinohen decarboxylase
Accumulated substrate in porphyria cutanea tarda
Uroporphyrin (tea-colored urine)
Signs and symptoms of porphria cutanea tarda
Blistering cutaneous photosensitivity (most common)
Which enzymes in heme synthesis are mitochondrial?
ALAS (RLS), Ferrochelatase
Enzyme affected in congenital erythropoietic porphyria
Uroporphyrinogen cosynthase
The first 2 enzymatic steps in the breakdown of heme
- Heme oxygenase (requires Fe2+, NADPH); gives off CO
2. Biliverdin reductase (NADPH)
Biliverdin color is…
Bilirubin color is…
Green
Orange/Yellow
What is the underlying reason for why people turn yellow in jaundice?
Pigment deposition in connective tissue
2 drugs which can induce kernicterus
- Salciylates
2. Sulfonamides
Which drug can induce the enzyme UDP glucournyl transferase (bilirubin metabolism)?
Phenobarbital
Rank the severity of: Crigler-Najjar 1, 2, Gilbert’s
Most severe: CN 1
Least severe: Gilbert’s
A defect in the ABC transporter with respect to bilirubin metabolism results in…
Dubin-Johnson Syndrome
What is the rationale for light therapy in newborn jaundice?
Can make bilirubin into a more polar compound for excretion (without enzymatic activity)
After bilirubin is deposited in the large intestine, it is de-conjugated to…
Urobilinogen –> stercobilin (feces)
*10% reabsorbed into portal blood –> urine (urobilin)
Four major alpha-1 serum proteins
- A1AT
- AFP
- Transcortin
- Retinol binding protein
AFP is increased/decreased with Down Syndrome and increased/decreased with NTD
Decreased in Down
Increased in NTD
Alkalosis can lead to hypocalcemia because…
Albumin becomes more negative and hence binds more Calcium
Three major alpha-2 serum proteins
- Alpha-2 macroglobulin
- Cerruloplasmin
- Haptoglobin
Three major beta serum proteins
- Transferrin
- Hemopexin
- LDL (beta lipoprotein)
Aside from storage of copper, cerruloplasmin has this type of activity on iron.
Ferroxidase activity: Fe2+ to 3+
Haptoglobin binds
Hemopexin binds
Hapto: Free Hb
Hemo: Free heme
Which clotting factors are synthesized by the liver?
5, 7, 9, 10, PT, fibrinogen
With ETOH usage: increased/decreased
- Beta oxidation
- FAS
- VLDL
- Decreased beta-oxidation with inc. NADH
- Increased FAS with inc. acetyl coA
- Decreased VLDL
In prolonged starvation, the protein sparing effect is observed. Explain.
Brain can use ketone bodies to generate glucose without breaking down muscle protein.
Where in the hepatocyte does ketogenesis occur?
Mitochondria
What is the fate of acetoacetate, beta-hydroxybutyrate and acetone?
Reconverted to acetyl coA –> TCA cycle
In order to form ketone bodies, is there a high or low NADH:NAD ratio?
High
Hormone sensitive lipase is stimulated/inhibited by insulin
Inhibited by insulin; stimulated by epinepherine.
*Active = phosphorylated
What enzybe converts acetoacetate to acetoacetyl coA in ketone body utilization?
Thiophorase
Can the brain use FFA’s?
No
What are the steps in making acetyl coA from fatty acids? Describe the location of each step.
- FA –> Fatty acyl coA [fatty acyl coA synthase] (cytosol)
- Fatty acyl coA –> CPT-1 –> acyl carnitine (outer MM)
- Acyl carnitine –> translocase –> acyl carnitine (inner MM)
- Acetyl coA (CPT2) inner MM
CPT-1 is inhibited by what enzyme?
Malonyl coA
Beta-oxidation of fatty acid steps
- Oxidation (MCAD) – FAD
- Add water
- Oxidation – NAD
- Cleavage
Each cycle of beta-oxidation produces how much acetyl coA, FADH and NADH
2, 1, 1
The number one AR enzyme deficiency (think beta-oxidation)
MCAD: dibarboxylic acids in urine, CK-MM, severe fasting hypoglycemia, hypoketonemia
Primary carnitine deficiency, CPT-1, CPT-2
Cannot oxidize long chain fatty acids
CPT-1: liver: systemic early presentation
CPT-2: muscle: cardiomyopathy later presentation
Jamaican vomiting sickness
Ackee fruit: hypoglycemia and vomiting; inhibits MCAD
Odd chain fatty acids are metablolized in this pathway
Propionyl coA -biotin-> MM CoA -B12-> Succs CoA
VLCFA are metabolized in this organelle. What syndrome is associated with a defective biogenesis of this organelle?
Peroxisome; Zellweger syndrome
Differentiate between alpha and omega oxidation of FA’s. Name a disease associated with alpha oxidation?
Alpha: Branched chain FA’s [phytanic acid from dairy in the peroxisome; cannot metabolize in Refsum disease]
Omega: alternative pathway when beta- isn’t active; results in increased dicarboxylic acids in the urine.
Refsum disease
Alpha oxidation defect; cannot metabolize branched chain fatty acids
Describe the trinucleotide repeat expansion diseases.
X-Girlfriends First Aid Helped Ace My Test
Fragile X: CGG
Fred Ataxia: GAA
Huntington: CAG
Myotonic dystrophy: CTG
Short term regulation of fatty acid synthesis
Activate: Citrate polymerized
Inactivate: Palmityl coA monomers (LCFA)
RLS of FAS
Acetyl CoA Carboxylase
The enzyme FAS is active as a monomer or dimer
Dimer
Treatment of ethylene glycol or methylene poisoning
- Alcohol
2. Fomepizole (compet inhibitor of alcohol dh)
Methanol is oxidized to…
Formaldehyde; leads to mental and visual disturbances [irreversible blindness]
Ethylene glycol is found in antifrereze. Ingestion can lead to…
Calcium oxalate stones and renal failure
Which cytochrome enzyme metabolizes alcohol?
CYP2E1
Differentiate between acetaldehyde DH1 & DH2
DH1: cytosol, higher Km
DH2: mitochondria, lower Km
Differentiate between phase I and phase II metabolism in the liver.
Phase I: CYP450
Phase II: Conjugation, UDP, PAPS, glutathione
What is the consequence of alcohol poisoning?
Very high levels of cytosolic NADH prevent GNG, pyruvate generation (from lactate).
How are fatty acids transported in the blood?
Bound to albumin
The formation of 3-beta-hydroxybutyrate uses/forms NADH; whereas the utilization of 3-betahydroxybutyrate uses/forms NADH
Uses; Forms
Why cannot the liver use ketone bodies?
It lacks thiophorase (succinyl CoA acetoacetate CoA transferase)
In addition to the liver, where is GNG performed in prolonged fasting?
Kidney
With respect to a fast, the metabolic fuels present at the beginning of a fast, which stores are the highest: sugar, fat, protein?
Fat
When are liver glycogen stores depleted during a fast?
1 day
Protein energy malnutrition leads to variable clinical conditions with extreme forms. What are the 2 major forms?
- Marasmus: protein-calorie; energy deficiency is predominant
- Kwashiorkor: protein is predominant
When children look severely starved and show less than 80% of standard weight they have:
Marasumus
B1 deficiency
Beri-Beri
B2 deficiency
Cheilosis (B2)
B3 deficiency
Pellagra (Niacin)
Vitamin C deficiency
Scurvy
Microcytic anemia can develop with Fe, and what other element and vitamin?
B6, Cu
Reduced response to infections can result from a deficiency of what elements?
Fe, Se, Zn
Poor wound healing can result from a deficiency of what element?
Zn
Night blindness can result from a deficiency of what vitamin?
Vitamin A
The fat soluble vitamins.
A, D, E, K
What are the formal names for:
Vitamin B1, B2, B3, B5, B6, B7 B9, B12; Vitamin C
B1: Thiamine B2: Riboflavin B3: Niacin B5: Pantothenic acid (CoA) B6: Pyridoxine B7: Biotin B9: Folate B12: Cobalamin C: Ascorbic acid
The transport and storage form of vitamin A
Retinol
Hypervitamintosis A
Headaches (can mimic brain tumors), dry & pruritic skin, enlarged liver, can cause spontaneous abortions
Should vitamin A supplements be given in pregnancy?
No
Differentiate between vitamin D2 & D3
D2: plants: ergocalciferol
D3: animals: cholecalciferol
What is the precursor for cholecalciferol synthesis in the skin?
7-dehydrocholesterol
What is the sequence of events in calcitriol synthesis?
7-DH cholesterol –> Cholecalciferol –> 25 –> 1
Bow-legged deformity, rachitic rosary, pigeon chest deformity, frontal bossing
Vitamin D deficiency
The most important role of vitamin E
Anti-oxidant: prevents peroxidation of lipids; scavenges free radicals
Deficiency of vitamin E manifests as
Hemolytic anemia (abnormal cell membrane); reduced DTR & gait problems 2/2 axonal degeneration
The most serious complication of hemorrhagic disease of the newborn.
Intracranial bleeding
Name 2 mechanisms of vitamin K deficiency in adults
- Fat malabsorption
2. Broad spectrum antibiotics
What vitamin acts as a coenzyme for the hydroxylation of proline and lysine in collagen?
Vitamin C
What vitamin is required for the absorption of Fe?
Vitamin C
The 2 vitamin deficiencies that can result in very similar clinical picture of perifollicular hemorrhages, bleeding, etc.
Vitamin K
Vitamin C
Functions of B1
PDH, A-ketogluterate DH, branched chain alpha-keto acid DH
* transketolase (PPP)
Co-enzyme for transketolase in PPP
B1
Wet vs. Dry beri-beri
Wet: CV
Dry: polyneuropathy
What vitamin deficiency is common when polished rice is the major diet component?
Thiamine (B1)
Vitamin B2 pariticpates in what types of reactions
FAD (Oxidation/Reduction)
Riboflavin deficiency results in…
Cheilosis, glossitis, facial dermatitis
Niacin can be used therapeutically for Type 2B hyperlipoproteinemia because
It inhibits HSL
Niacin deficiency results in…
The 3 D’s:
Dermatitis (exposed areas of body – necklace like), Diarrhea, Dementia (degeneration of neurons in brain and spinal tracts), Death
Which amino acid can be used to synthesize NAD?
Tryptophan
Corn based diets can cause…
Pellagra
Patients with Hartnup’s disease and carcinoid syndrome may p/w
Pellagra
Biotin, or B7, is the prosthetic group for most… reactions (name the type of reaction)
Carboxylation
Multiple carboxylase deficiency results from a deficiency of what vitamin?
Biotin
Pyruvate carboxylase, Acetyl-coA carboxylase, propionyl coA carboxylase
A patient who ingests a very large amount of egg whites will p/w a deficiency of what vitamin? Why
Biotin; avidin inhibits absorption of biotin
Reactions using vitamin B6
Transamination, AA decarboxylation (synthesis of NT), condendation (ALAS in heme synthesis), conversion of homocysteine to cystein
Children with homocystinuria can respond to dietary supplementation of what vitamin?
B6
S/S of pyridoxine deficiency
Microcytic anemia, peripheral neuropathy, increased risk of CV dz (2/2 plasma homocysteine), seizures
T/F Because B12 is only synthesized by microorganisms, not present in plants, vegans have a high risk of deficiency
True
Deficiency of what element: Muscle weakness, neurologic defects, hypopigmentation, abnormal collagen cross-linking
Cu
Deficiency of what element: Acrodermatitis enteropathica, growth retardation, infertility
Zn
Important co-factor for: cytochrome c, SOD, lysyl oxidase, tyrosinase, dopamine beta-hydroxylase
NT synthesis
Kinky hairy syndrome
Copper deficiency; inherited defect in copper absorption from the GIT (X-linked)
Gene for Wilson disease is located on chromosome
13
Essential fructosuria vs. Hereditary fructose intolerance
Essential: fructokinase (benign)
Hereditary: F-1-P [aldose b]
Describe the role of aldose reductase
Aldose reductase converts glucose and galactose to sorbitol and galacitol, respectively; lens/cataracts lack sorbital DH
How is galactose typically absorbed?
SGLT-1
Non-classical galactosemia vs. Classical galactosemia
Non-classical: galactokinase (early cataracts)
Classical: glactose 1-p-uridyl transferase [jaundice, hepatomegaly, neuro damage 2nd-3rd week of life]
In hospital, at birth, babies’ heels are pricked to test for…
Classical galactosemia
_________________ activity in RBC can be used as an index of nutritional thiamine status.
Transketolase
The oxidative part of the pentose phosphate pathway generates
NADPH oxidase
Differentiate between chronic granulomatous disease and G6PD deficiency.
CGD: NADPH oxidase
G6PD deficiency: inability to regenerate reduced glutathione (GSH) necessary for the enzyme glutathione peroxidase when detoxifying H2O2 in RBC’s
Heniz bodies
Present in RBC’s undergoing oxidative stress in patients with G6PD deficiency
G6PD A- vs. Mediterranean
A-: Mild
Mediterranean: Severe
MPO deficiency p/w what specific type of recurrent infection?
Recurrent Candida infections
CGD, also known as Bridges-Good Syndrome p/w
Recurrent PNA, Aspergillus
Describe the potential fate of H2O2
MPO (Cl-), Glutathione peroxidase (organic peroxides), Catalase, Fenton (combine with Fe2+), Haber-Weiss (combine with superoxide)
T/F iNOS combines arginine and citruilline to form NO2 radical
True
T/F Mitochondrial DNA is more susceptible to DNA damage in comparison to nuclear DNA.
True. Lack of histones
Give several examples of non-enzymatic free radical scavengers
Uric acid, glutathione, bilirubin, melatonin
The most dangerous free radical
Hydroxyl free radical
