Biochem Factoids Flashcards
Type I collagen
Strong; skin, bone, dentin
Type II
Slippery: cartilage, vitreous, nucleus pulposus
Type III
Bloody; blood vessels, skin, uterus, fetal tissue, granulation tissue
Type IV
Basement membrane
What type of protein processing occurs in RER
N-linked oligosaccharide addition
Nuclear localization signal
4-8 Aas of lysine, arginine, and protein (essential for proteins bound for nucleus such as histones)
Golgi protein modification
Modifies the N-oligosaccharides on Asparagine
Golgi protein addition
O-oligosaccharides are added to Serine and Threonine
Golgi targeting to lysosome
Mannose-6-phosphate, defect results in I-cell disease; clouded cornas, coarse facial features, restricted joints, high plasma lysosomal levels.
G1 to S phase
Cyclin D binds and activates CDK4 which phosphorylates Rb to release it from E2F –> synthesis of S components. Cell officially enters S phase when CDK2 is activated by Cyclin E
G2 to M phase
Mediated by Cyclin A and Cyclin B
Chediak-Higashi syndrome
Problem with microtubule assembly; Parital albinism, peripheral neuropathy, recurrent pyogenic infection
Kartageners syndrome
immotile cilia due to dynein arm defect. Infertility, bronchiectasis, and recurrent sinusitus; Assoc with situe inversus (10% have transposition of great vessels)
Preprocollagen
the newly synthesized alpha chain in the RER
ER Collagen Processing
Hydroxylation (vit. C) of proline and lysine; glycosylation of hydroxyllysine residues and formation of procollagen via hydrogen and disulfide bonds (this is the triple helix of 3 alpha chains) procollagen = triple helix
Extracellular processing of procollagen
The procollagen is proteolytically cleaved of its terminal regions to an insoluble tropocollagen; the process is completed by cross-linknig it to other molecules by lysyl oxidase (copper dependent) to make collagen fibrils
Elastin
Rich in proline and glycine, nonhydroxylated (vs. collagen). Tropoelastin with fibrillin scaffold – Desmosin crosslinking of elastin accounts for its properties
Red infarcts
In tissues with multiple blood supplies or in reperfusion after infarction. Commonly, lungs, liver, and Intestins
Pale infarcts
In tissues with single blood supply like heart, kidney, spleen
Amino acids modified by golgi apparatus
Asparagine, threonine, serine
glycolysis rate limiting step
Phosphofructokinase-1 (PFK-1)
Gluneogenesis rate limiting enzyme
Fructose-1,6-bisphosphatase
TCA cycle rate limiting enzyme
isocitrate dehydrogenase
Glycogen synthesis rate limiting enzyme
glyogen synthase
Glycogenolysis rate limiting enzyme
glycogen phosphorylase
HMP shunt rate limiting enzyme
G6PD
Rate limiting step of de novo pyrimidine synthesis
Carbamoyl phosphate synthetase -II
Rate limiting step in purine synthesis
Glutamine-PRPP amidotransferase
Urea cycle
Carbamoyl phosphate Synthetase I
FA synthesis rate limiting step
Acetyl-CoA carboxylase
FA oxidation rate limiting step
Carnitine acyltransferase I
Ketogenesis rate limiting step
HMG-CoA synthase
Cholesterol synthesis rate limiting step
HMG-CoA reductase
malate-astpartate shuttle produces
32 ATP per glucose
Glycerol 3 phosphate shuttle
30 ATP per glucose
Purine Ring composition
Aspartate, CO2, Glutamine (nitrogen), glycine
Pyrimidine ring composition
Glycine and carbamoyl phosphate
Enzyme blocked by 6-MP
PRPP synthase
Mycophenolate mophetil inhibits what enzyme
PRPP synthase
TATA
promoter 25 base pairs upstream
CAAT
70 to 80 base pairs upstream
Enhancers and repressors location
can be anywhere within the gene upstream or downsream
tRNA characteristics
75 to 90 nucleotides, cloverleaf, 3’-CCA- aminoacyl end, 5’ guanosine terminal
tRNA charging
Aminoacyl-tRNA synthetase; scrutinizes aa before and after binds to tRNA (if accidentally mischarged it will place in wrong aa).
tRNA structure
T(psi)C arm- sequence of thymidine and pseudoridine (3’ side); D-arm (5’ end) has dihydrouracil and acetylcytosine; arms are responsible for clover structure
Post-translational modificaiton in the RER
N-oligosaccharide addition
Modification in Golgi
N-oligosaccharide on Asparagine; O-oligosaccharide on serine and threonine; Mannose-6-phosphate for lysosome targeting
I-cell disease
failure of addition of mannose-6-phosphate to lysosome proteins; coarse facial features, clouded corneas. Restricted joints, high lysosomal enzymes in plasma
Peroxisome
Degradation of long fatty acids and amino acids
Proteasome
degradation of proteins marked by ubiquitin
Aerobic metabolism of glucose produces…
32 ATP via malate aspartate shuttle (heart and liver); 30 ATP via glycerol-3-phosphate shuttle (muscle)
Hexokinase
ubiquitous, low Km (high affinity) but low Vmax (low capacity)
Glucokinase
Liver and beta cells of pancreas. Low affinity (high Km) but really high Vmax (high capacity)
Hunter’s
Iduronate sulfatase deficiency; heparan sulfate and dermatan sulfate; XR; Mild hurler’s with aggressive behavior and no corneal clouding
Hurler’s
alpha-L-iduronidase deficiency; Heparan sulfate; AR; developmental delay, corneal clouding, gargoylism (flat face, depressed nasal bridge and bulging forehead), hepatosplenomegaly, airway obstruction
Krabbe’s
galactocerebroside buildup from lack of beta-galactocerebrosidase; peripheral neuropathy, developmental delay, optic atrophy, globoid cells (macrophages engorged with multiple nuclei in parenchyma and around blood vessels)
Metachromatic leukodystrophy
lack of arylsulfatase-A; Cerebroside sulfate buildup; demyelination, dementia, ataxia. AR
Niemann-Pick Disease
sphingomyelinase deficiency buildup of sphingomyelin; nerodegeneration, ashkenazi, hepatosplenomegaly, cherry red macula, foam cells
Tay Sachs
hexoaminidase A deficiency; GM2 buildiup; NO HEPATOSPLENOMEGALY (vs. Neimann pick); Cherry red macula, nervous degeneration, developmental delay, onion skin lysosomes
mitochondrial inheritance diseases
Leber’s hereditary optic neuropathy (acute loss of central vision); myoclonic epilepsy, mitochondrial encephalopathy. Ragged red fibers on microscopy. Often due to failure in oxidative phosphorylation. All offspring
codominance
2 alleles, equal dominance; ie ABO blood groups
variable expression
severity of the phenotype varies form one to another; ie NF or Tuberous sclerosis
Plieotroy
one gene has more than one effect on phenotype; ie PKU
Locus heterogeneity
Mutations at different loci can produce same phenotype; Ie. Marfan’s, MEN 2B, Homocystinuria (all three of these produce similar Marfan body habitus)
Mosaicism
cells have different genetic makeup in body;
Imprinting
uniparental disomy or inactivation or deletion of genes on Chromosome 15; Phenotype differences depend on wether mutaiton comes form mother or fathe
Prader-Willi
Paternal allel should be active but is deleted; has normally inactivated maternal allel; mental retardation, hyperphagia, obesity, hypogonadism, hypotonia; one of few causes of childhood osteoperosis
Angelman’s syndrome
Maternal allel is deleted, normally inactivated paternal allele; Mental retardation, seizures, ataxia, inappropriate laughter
Rasburicase
Analog of Urate Oxidase (not present in humans), can catalyze uric acid into allantoin to help prevent renal toxicity in the case of tumor lysis syndrome. Allopurinol can be given as well.
Denosumab
Monoclonal antibody against RANKL to prevent osteoclast activation.
amino acids involved in the urea cycle
Aspartate (donates an NH3 to Citruline), and Argenine (produces urea and ornithine)
Electron transport chain complexes
I: NADH, II: Succinate dehydrogenase (FADH2) and CoQ, III: CoQ to III to Cytochrome C to IV (reduction of O2) to V (phosphorylation of ADP)
Inhibitors of electron transport complexes
Oligomycin (Complex V); Rotenone, amytal(barbituate), antimycin A, MPP from MPTP, CO, H2S, and CN-
Oxidative phosphorylation uncouplers
Thermogenin found in brown fat, aspirin, 2,4-DNP found in wood preservatives
Acute Intermittent Porphyria
HMB synthase or Uroporphyrinogen I synthase; buildup of porphobilinogen; abdominal pain, red-wine urine upon standing, increased urinary ALA and PBG, neurologic manifestations; can be precipitated by drugs like barbital, griseofulvin, and phenytoin, and alcohol.
ALA synthase regulation
substrates are glycine and Succinyl-CoA; Inhibited by glucose and heme; promoted by EtOH, Barbituates, and hypoxia
Porphyria cutanea tarda
Uroporphyrinogen decarboxylase deficiency; buildup of uroporphyrinogen III; Photosensitivity, blisters
JAK2 activation mutations relate to these disorders
All chronic myeloproliferative disorders except for CML (bcr-abl); Essential thrombocytosis, polycythemia vera, and Primary myelofibrosis (splenomegaly that causes early satiety, hepatomegaly, anemia and bone marrow fibrosis)
Ruxolitinib
JAK2 inhibitor approed for treatment of primary myelofibrosis
substrates for transcarbamoyl phosphate synthetase II
Glutamine and CO2 and ATP (for Pyrimidine synthesis)
substrates for transcarbamoyl phosphate synthetase I
CO2 and ATP and NH4+ (for Urea cycle)
Orotic aciduria enzymes
Orotate phosphoribosyl transferase (converts Orotic acid to UMP) an Orotidine 5’-phosphate decarboxylase[will NOT have hyperammonemia symptoms]; Ornithine transcarbamoyl transferase (in urea cycle so will cause hyperammonemia)
Steps of collagen synthesis and cellular location
alpha preprocollagen chains of Gly-X-Y (RER); Hydroxylation or pro and lys (ER); Glycosylation of lysine (ER); Assembly of procollagen (triple helix via disulfide bond formation in C-terminal propeptide); Secretion via golgi of procollagen into ECM; N and C terminal propeptide cleavage by propeptidase into insoluble tropocollagen; collagen fibril is cross-linked by lysyl oxidase to make collagen fibril polymers (copper dependent enzyme)
The main allosteric activator of Carbamoyl phosphate synthetase I
N-acetylglutamate (the main regulator of the urea cycle)
Kozak sequence
Methioning AUG codon is positioned near Kozak sequence b/c Kozak sequence (GccRcc, R=adenine or guanine), it serves to initate translation by helping mRNA bind to ribosomes, when there is a mutation in this sequence in beta-heme it can result in beta-thalassemia
Translocation step in translation
Requires eEF2 and GTP
Peptide bond formation on ribosome
catalyzed by peptidyl transferase on eurkaryotic ribosomes
bisphosphoglycerate mutase
enzyme that forms 2,3-BPG from 1,3-BPG from glycolytic pathway to be used by erythrocytes
Main allosteric activator of the key first step of gluconeogensis
Pyruvate carboxylase is activated by excess acetyl-CoA signaling a well fed state
How is oxaloacetate shuttled out of mitochondria for gluconegenesis in cytoplasm
oxaloactetate to Malate by malate dehydrogenase then malate is reconverted to oxaloacetate in the cytoplasm where it undergoes conversion to PEP by PEPCK (Uses GTP)
Four main metabolites of pyruvate
Lactate (regeneration of NAD+), Acetyl-CoA (FA synthesis, cholesterol synthesis, TCA), Oxaloacetate (gluconeogenesis), Alanine (in muscle cells to carry NH3 away to liver)
Key regulators of PFK-1
F2,6BP; made from F6P by PFK-2, PFK-2 is activated in the fed state (dephosphorylated) and inactivated in the starving state (phosphorylated via glucagon increase of cAMP and PKA). F2,6BP is deactivated by FBPase-2 which is active in starve state (phosphorylation) and inactive in fed state (dephosphorylation).
Cofactors for Pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and Branched-chain alpha-ketoacid dehydrogenase
Lipoic acid, Thiamine, CoA, FAD, NAD
Products of B6 conenzyme reactions
GABA from glutamate, dopamine from dopa, heme from ALA synthase and glycine, histamine from histidine, Niacin from tryptophan
alkaptonuria
deficiency in homogentisic acid oxidase (a metabolite of Tyrosine on its way to fumarate); Usually a benign disease; find dark brown pigment in connective tissue and SCLERA because when homogentisate binds to collagen it turns dark; urine turns black on prolonged exposure to air. Can present with debilitating arthralgias
Roles of NADPH
anabolic reactions such as cholesterol and FA synthesis, reduction of glutathione, and production of oxidative burst
Where are Urea’s nitrogens from?
Ammonium that is used to form carbamoyl phosphate and transferred to citruline; And Aspartate which donates an amino group to citrulline to form arginosiccinate.
How does the nephron rid of ammonium
Glutamine carries ammonia from peripheral tissues to the kidney where it is hydrolyzed by glutaminase in the tubule to produce glutamate and free ammonium ion where it is excreted in urine.
Two enzymes B12 is essential for
homocystein methyltransferase (to make methionine from homocysteine, also invovles folate); Methylmalonyl-CoA Mutase (or isomerase) to make succinyl coA from methylmalonyl-CoA
differentiating Cori’s disease from other glycogen storage diseases
there is normal lactate levels and biopsy shows accumulation of short outer dextrin-like structures in the cytosol of hepatocytes with absence of histopathological fatty infiltration of the liver. Debranching enzyme affects liver and muscle cells but mainly presents with hepatocyte manifestations
Major biochemical defect in beta-thalaseemia
mutations affect the transcription, processing and translation of mRNA; this leads to decreased beta chain production
tetrahydrobiopterin is involved in what reactions
Phenylalanine to Tyrosine, tyrosine to Dopa; Tryptophan to Serotonin
Ach is made from
choline and acetyl-CoA from cholineacetyltransferase
Elastin versus collagen
Elastin can be stretched and recoil back; it is composed primarily of non-polar Aas gly, ala, and val. Also contains pro and lys. Fibrillin is the foundation/support. Desmosine corsslinking accounts for properties allowing it to recoil after being stretched. In skin, blood vessels, lungs. Differs from collage: very few proline and lysine are hydroxylated, no triple helix, hydroxylation, glycosylation, and intercahing disulfide bridges at C-terminus do not occur in elastin as in collagen.
myc
transcription factors
Ras
G-protein
Pyruvate dehydrogenase deficiency
congenital or acquired (ie alcohol); neurologic defects; Tx: increase ketogenic Aas (Lysine and Leucine)
Essential AA
Met, Val, Arg, His; Ile, Phe, The, Trp; Leu, Lys
Purely ketogenic Aas
Lysine, Leucine
Glucogenic and Ketogenic Aas
Ile, Phenylalanine, Threonine, Tryptophan
Glucogenic Aas
Methionine, Valine, Arginine, Histidine
Two ways the brain buffers ammonia
First alpha-ketoglutarate can be combined with NH4+ to yield glutamate; Glutamate itself can be used as a buffer in the astrocyte for ammonium by combining to make glutamine. Glutamine can be reconverted back to glutamate by glutaminase in the neuron for use by the pre-synaptic neuron
Ras-MAP kinase
Ras is a G-protein that binds GTP/GDP and is part of tyrosine kinase cascade where the tyrosine kinase receptor autophosphorylates itself, MAP is eventually activated and enters the nucleus where it can interact with the DNA
Sorbitol is produced and metabolized by what enzymes
Glucose or galactose are converted to sorbitol by aldose reductase. Sorbitol is then converted to Fructose by sorbitol dehydrogenase. Tissues like schwann cells, kidneys, etc. do not contain sorbitol reductase and are at risk for osmotic damage
A differentiating feature between Tay-Sachs and Neimann-Pick’s disease is
Neimann-Pick’s disease presents with hepatosplenomegaly whereas Sachs has no hepatosplenomegaly
NADPH Oxidase
Deficient in Chronic Granulomatous Disease; O2 to O2 radical
Superoxide dismutase
Converts O2radical into H2O2; second step in respiratory burst
Myeloperoxidase
Combines H2O2 with Chloride to form hypochlorous acid; final step in oxidative burst
Asparaginase treatment of Lymphoneoplastic cells
asparaginase breaks down normal asparagine to urea and ornithine; this is a useful treatment because lymphoblastic cells can not synthesize own asparagine so you are removing their supply
Deamination of glutamate gives
alphaketoglutarate
Deamination of alanine gives
Pyruvate
Cori Cycle
uses alanine and glutamate from muscle and transfers nitrogen to the liver by converting alpha ketoglutarate to glutamate and pyruvate to alanine; these transamination reactions all require B6
Treatment for Hyperammonemia
Benzoate, Phenylbutyrate (both bind amino acid); limit protein intake; Lactulose acidifies the GI and traps NH4+ in the colon for excretion
Cystinuria
AR defect in tubular transporter for cysteine, ornithine, lysine, and arginine in PCT of kidneys; hexagonal crystals of cysteine staghorn calculi; Acetazolamide to alkalinize the urine
Enzymes involved and location of Ketogenesis
Occurs in the mitochondria from Fatty acids. Fas go through Beta-oxidation and the Acetyl-CoA units are used to synthesize HMG-CoA via HMG-CoA synthase (same as for cholesterol); HMG-CoA is converted to acetoacetate by HMG-CoA Lyase (while cholesterol synthesis would start with HMG-CoA reductase); Acetoacetate can make beta-hydroxybutyrate with reduction by NADH. From there it enters bloodstream
Glycogen Phosphorylase Kinase regulation
phosphorylated by PKA via glucagon or adrenergic activation a la cAMP. The phosphorylation is activated and goes on to phosphorylate glycogen phosphorylase which does its business. Calcium/calmodulin also will activate Glycogen phosphorylase kinase in muscle; Insulin through its receptor tyrosine kinase will activate protein phosphatase which dephosphorylates glycogen phosphorylase kinase and glycogen phosphorylase
Carnitine deficiency
Can not transport LCFAs into mitochondira results in toxic accumulation; Weakness, hypotonia, Hypoketotic, Hypoglycemia
Acyl-CoA dehydrogenase deficiency
hypoglycemic hypoketonemia; increase in dicarboxylic acids and decrease in glucose and ketones
Rate limiting step in FA oxidation
Carnitine acyetyl transferase (inhibited by malonyl-CoA)
FA synthesis regulation
Acetyl-CoA carboxylase (uses biotin) is rate limiting step; Forms malonyl-CoA from Acetyl-CoA; Citrate moves from mitochondria via citrate shuttle to cytosol
Protein and carbs versus fat as kcal energy source
1 g of protein and carbohydrates = 4 kcal; 1 g of fate = 9 kcal
Name steps of heme breakdown from RES to Excretion in feces
Heme to biliverdin -> bilirubin -> transported to liver bound to albumin -> conjugated by UDP glucuronyl transferase -> conjugated bilirubin -> excretion to feces -> urobilinogen -> reabsorption to liver for reuse, feces and urine for color.
Crigler Najar
Absence of UDP Glucuronyl transferase
Gilbert’s
Low levels of UDP-Glucuronyl transferase
Rotor’s and Dubin-Johnson syndrome
Defective secretion of direct bilirubin into feces
Apo E
Mediates remnant uptake; seen on chlyomicrons
Apo A-1
Activates LCAT (Lecithin-cholesterol acyltransferase) which catalyzes esterification of cholesterol; Found on HDL
Apo C-II
Lipoprotein Lipase cofactor - degrades TG circulating in chlyomicrons and VLDLs
Apo B-48
Mediates chlyomicron secretion from enterocytes; found on chlyomicrons; deficiency in this leads to abetalipoproteinemia
Apo B-100
Binds LDL receptor; Found on LDL
Type I dyslipidemia: Hyper-Chlyomicronemia
Deficiency in Apo C-II or LPL; Increased Chlyomicrons and TG, and cholesterol; Causes pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas (no increased atherosclerosis risk)
Type Iia - Familia hypercholesterolemia
AD, Decreased LDL receptors; cholesterol increase in blood; atherosclerosis, xanthomas and corneal acrus
Type IV - Hypertriglyceridemia
Hepatic overproduction of VLDL; VLDL is elevated and TGs
Abetalipoproteinemia
ApoB-48 or Apo-B100; AR; Accumulation of chlyomicrons within enterocytes; failure to thrive, steatorrhea, acanthcytosis of RBCs, ataxia, night blindness (due to Vit A and Vit E deficiencies)
