Biochem Flashcards
DNA
histones - lysine and arginine
- 8 histones in a nucleosome, H1 is the linker
heterchromatin - highly condensed, increased methylation, decreased acetylation
- ex Barr bodies
euchromatin - transcription active (look white on EM)
methylation
- methylation at CpG islands - represses transcription
- DNA methylated at C and A = old strand
nucleoSide - base + sugar cytosine - NH2 - uracil adenine - NH2 = guanine uracil + methyl = thymine GAG = glycine, aspartate, glutamine are necessary for purine synthesis
methionine and tryptophan - only coded by 1 codon
genetic code universal - except mitochondria
De novo purine and pyrimidine synthesis
PYR:
requires aspartate
1) glutamine + CO2 –> carbamoyl phosphate, by carbamoyl phosphate synthetase 2
2) CP + aspartate –> orotic acid
3) orotic acid + PRPP –> UMP –> UDP or CTP
4) UDP –> dUDP by ribonucleotide reductase
5) dUDP –> dUMP –> dTMP (thymidylate synthase)
leflunoamide - inhibits dihydroorate dehydrogenase, cant produce orotic acid
MTX, TMP, Pyrimethamine (Protozoa) - DHF reductase inhibitors, cant make dTMP
5-FU - forms 5-F-dUMP, inhibits thymidylate synthase
……………………………………
PUR:
requires GAG and THF
1) ribose 5-P –> PRPP –> IMP –> AMP or GMP
6-mercaptopurine, azathroprine (pro-drug)
mycophenolate and ribavirin - inhibit IMP dehydrogenase, cant make GMP
hydroxyurea - inhibits ribonucleotide reductase
- affects purine and pyrimidine synthesis
purine salvage
HGPRT
- guanine –> GMP
- hypoxanthine –> IMP
Lesch-Nyhan syndrome (XR) - absent HGPRT
- results in excess uric acid production - guanine and hypoxanthine are degraded instead of recycled
- Hyperuricemia (orange sand crystals in diaper), Gout, Pissed off (aggressive, self-mutilating), Retardation, dysTonia
- treat with XO inhibitor
hypoxanthine –> xanthine –> uric acid –> urine
- allopurinol and febuxostat inhibit XO
- lose-dose ASA and probenecid prevent uric acid excretion into urine
ADA - adenosine deaminase, required for degradation of adenosine and deoxyadenosine
- dATP is toxic to lymphocytes
- cause of AR SCID
DNA replication
CAAT/TATA box - promoter, origin of replication
- eukaryotes have multiple origins
- promoter is where RNA pol2, TFs bind
enhancer (binds TFs), silencers - can be located anywhere, even in intron
DNA pol 3 - prokaryotes ONLY - has 3-5 nuclease activity DNA pol 1 - prokaryotes ONLY - degrades RNA primer and replaces it with DNA - 5-3 exonuclease
telomerase - RNA-dep DNA polymerase
- TTAGGG repeates
mutations in DNA
start codons - AUG eukaryotes
- N-formylmet - stimulates neutrophil chemotaxis
stop codons: (U Go Away)
UAG
UGA
UAA
frameshift mutation - DMD, Tay-Sachs, cystic fibrosis
splice site - intron retained
ssDNA repair:
1) nucleotide excision repair - occurs in G1 phase
- endonculeases
- xeroderma pigmentosum
2) base excision repair
- base specific glycosylase
- AP-endonuclease cleaves 5’ end, lyase cleaves 3’ end –> one or more surrounding nucleotides are cleaved
- DNA pol-b and ligase seal gaps
- occurs throughout cycle, used to repair spontaneous deamination - deamination can occur to excess nitrites
3) mismatch repair - occurs in G2 phase
- Lynch syndrome
nonhomologous end joining repairs dsDNA breaks
- defective in ataxia telangiectasia, BRCA1 mutations, Fanconi anemia
lac operon
E coli- glucose is preferred substrate
- when glucose is absent and lactose is present - lac operon is activated to switch to lactose metabolism
low glucose –> adenylate cyclase … activates CAP (catabolite activating protein) –> transcription
high lactose –> binds repressor protein so that it cant bind to operator region on DNA–> increased transcription
RNA
RNA pol 1 = rRNA
RNA pol 2 = mRNA
- a-amantin (mushrooms) - inhibits RNA pol 2, causes severe hepatotox
RNA pol 3 = 5S rRNa, tRNA
prokaryotes have 1 RNA pol
- rifampin inhibits it (DNA-dep RNA pol)
actinomycin D inhibits RNA pol in eukaryotes and prokarytotes
1) cap
2) cap methylation
3) AAUAAA = polyadenylation signal
4) splicing (GU…AG)
P-bodies - cytoplasmic, quality control bodies
- contain exonucleases, decapping enzymes, and microRNAs
- microRNA - target the 3’UTR for degradation or translational repression (abnormal expression can cause cancer, ex silence a TS gene)
- miRNA exits nucleus double-stranded –> cleaved into a shorter helix by dicer –> individual strands are separated and incorporated into RISC
- exact match –> degradation
- partial match –> translational repression
small interfering RNA - also repress translation
splicing: GT….AG
- pre-mRNA + snRNPs
- antibodies to snRNPs = anti-Smith, highly specific for SLE
- anti-U1 RNP antibodies associated with mixed CT disease
tRNA
acceptor stem has CCA at end
T-arm = Tethers tRNA to ribosome, modified bases
D-arm - dihydrouridine residues, D-arm Detects tRNA by aminoacyl-tRNA synthetase
amino acid-tRNA bond has energy for formation of peptide bond
protein synthesis
initiation - initiated by GTP hydrolysis
1) IFs, 40S, initiator tRNA
2) IFs released when mRNA and 60s unit arrive
elongation - APE
- E site contains empty tRNA as it exits
- ATP charges tRNA
- GTP - tRNA translocation
termination - release factor
side note - HSPs are chaperone proteins
RER - Nissl bodies = RER of neurons, goblet cells and plasma cells are rich in RER
- N-linked oligosaccharides are added in the RER
cell cycle
cyclins - proteins that control cell cycle events, activate cyclin-dependent kinases
p53 induces p21 –> inhibits CDK –> hypophosphorylation of Rb and inhibition of G1-S progression
mitosis is the shortest phase
G0 - G1 (growth phase) - S - G2 - M
permanent cells - remain in G0, regenerate from stem cells
stable (quiescent) - enter G1 from G0, hepatocytes, lymphocytes
labile - never go to G0, divide rapidly with short G1
- bone marrow, gut, skin, hair follicles, germ cells
Golgi
modifies N-oligosaccharides on asparagine, adds O-oligosaccharides on serine and thr
adds mannose-6-P to proteins for trafficking to lysosomes
- I-cell disease (inclusion cell disease/mucolipidosis type 2) - defect in N-acetylglucosaminyl-1-phosphotransferase - Golgi doesnt P mannose residues
- proteins are secreted rather than sent to the lysosomes
- coarse facial features, clouded corneas, restricted joint movements, and high plasma levels of lysosomal enzynes
- fatal in childhood
signal recognition particle - ribonucleoprotein that shuttles proteins from ribosome to RER
COP1 - Golgi to ER
COP2 - ER to Golgi
clathrin coated vesicles - endosomes, Golgi to lysosomes
(cis golgi is the side closest to the smooth ER)
fatty acids
peroxisome - catabolism of very-long chain FAs (b-oxidation), branched chain FAs, aas, EtOH
- defects in neurological diseases - due to deficits in plasmogens (phospholipids in myelin)
- Zellweger syndrome - hypotonia, seizures, hepatomeg, early death
- Refsum disease - scaly skin, ataxia, cataracts/night blindness, shortening of 4th toe, epiphyseal dysplasia
cytoskeleton
microfilaments - actin, microvilli
IFs - cell structure, vimentin (mesenchyme including
macrophages and endothelial cells), desmin, cytokeratin, lamins, GFAPs, neurofilaments (neuroblastoma)
microtubules - movement (including protein trafficking), and cell division
- a/b tubulin dimers with 2 GTP bound
- dynein is retrograde (to nucleus) transport
- drugs: mebendazole, griseofulvin, colchicine, vincristine/vvinblastine (anticancer), paclitaxel (microtubules get constructed very poorly)
cilia: 9 doublets + 2, 9 triplets at base (below cell membrane)
- ATPase links peripheral doublets - bending of cilium with sliding of doublets
- Kartagener - female fertility decreased/ectopics, chronic ear infections, conductive hearing loss, etc.
NA/K ATPase
pump+P = 3 Na leave
pump dephosphorylated = 2K in
ouabain inhibits binding to K+ site - cardiac glycoside, toxin
collagen
most abundant protein in human body
type 3 collagen - reticulin so skin, bvs, uterus, fetal tissue, granulation tissue
type 4 - BM, basal lamina, lens
1) Gly-X-Y
2) hydroxylation of proline/lysine - vitamin C
3) glycosylation - of hydroxylysine residues and formation of triple helix (issues forming triple helix in osteogenesis imperfecta)
3) exocytosis into extracellular space
4) cleavage of disulfide-rich ends –> insoluble tropocollagen (problems with cleavage = Ehler’s Danlos)
5) cross-linking - Cu lysyl oxidase (Ehler’s Danlos, Menkes)
notes - proline adds kink, hydroxylysine allows for H-bonds
osteogenesis imperfecta (AD)
- COL1A1 and COL1A2 defects - decreased type 1
- hearing loss, teeth abnormalities (no dentin)
Ehlers-Danlos (AD, AR)
- joint dislocation, berry aneurysms, organ rupture, easy bleeding
- hypermobility type
- classical type - defect in type 5 collagen, joint and skin symptoms
- vascular type - vascular and organ rupture
Menkes disease (XR)
- impaired Cu absorption and transport duet to defective ATP7A
- brittle kinky hair, growth retardation, hypotonia
elastin
located…. in vertebral ligaments, vocal cords
rich in NONhydroxylated proline, glycine, and lysine residues
tropoelastin with fibrillin (glycoprotein) scaffolding - extracellular cross-linking
elastase
wrinkles of aging are due to decreased collagen and elastin production
Marfans - AD, subluxation of lens (up and temporal)
DNA IDs
Southern - cDNA (IDed with radiolabeled DNA probes)
Northern - RNA, can see gene expression
Southwestern - DNA-binding proteins
flow cytometry - commonly used in workup of hem abnormalities
- tagged antibodies, fluorescence and scatter measured
microarrays - can detect single nucleotide polymorphisms and copy number variations
FISH - can detect microdeletion, translocation, or duplication
Cre-lox expression - manipulate genes at certain development points
genetics vocab
codominance - a1-antitrypsin deficiency
expressivity - same genotype, diff phenotype (NF1)
penetrance - not all individuals with mutant genotype show it (ex BRCA1 does not always produce cancer)
loss of heterozygosity = 2-hit hypothesis (NOT true for oncogenes)
mosaicism - somatic and germline (assume if parents dont have disease)
- McCune Albright - mutation in G-protein signaling –> unilateral cafe-au-lait spots with ragged edges, polyostotic fibrous dysplasia, endocrinopathy
- lethal if occurs before fertilization - affects all cells
locus heterogeneity v.s. allele heterogeneity (different mutations at same locus the same genotype)
heteroplasmy - mtDNA
- mitochondrial myopathies - myopathy, lactic acidosis, CNS disease
- MELAS syndrome - failure of oxidative P –> mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, muscle biopsy shows ragged red fibers (accumulation of disease mitochondria)
uniparental disomy - kid has recessive disease when only one parent is the carrier
- heterozygous - mutation in meiosis 1
- homozygous - mutation in meiosis 2
p+q = 1, p2 + 2pq + q2 = 1
imprinting - only one allele is active, if active allele is deleted –> disease
- PW - paternal deletion or 25% due to maternal UPD, hypogonadism, hypotonia…
- Angelman - maternal deletion or 5% due to paternal UPD, inappropriate laughter, seizures, ataxia, severe ID
XD
hypophosphatemic (vitamin D resistant) rickets, fragile X, Alport
AD
…familial adenomatous polyposis, familial hypercholesterolemia, hereditary hemorrhagic telangiectasia
Li Fraumeni, MENs, NF1&2, TS, VHL
Huntington
AR
albinism, CF, glycogen storage diseases, Hurler, hemochromatosis, PKU, sphingolipidoses (except Fabry), Wilsons disease
thalassemias, Kartageners
XR
ornithine transcarbamylase def, Lesch-Nyhan
Fabry, Hunter, ocular albinism
Wiskott-Aldrich, Bruton agammaglobulinemia
hemophilia
DMD, BMD
lyonization - due to bar bodies
phosphorylase
- lase adds things
adds P without using ATP
synthetase - reaction using no energy source
glycolysis
produces 2pyruvate, 2ATP and 2NADH
making glucose-6-phosphate is the first step of glycolysis
- also the first step of glycogen synthesis
hexokinase - most tissues
glucokinase - liver, pancreatic b-cells
- decreased affinity (lower Km), higher Vmax (higher capacity)
- induced by insulin
- feedback NOT inhibited by G6P, inhibited by fructose-6-P
RLS = fructose-6-phosphate to fructose-1,6-BP, phosphofructokinase-1 (PFK1)
+ AMP + fructose-2,6-bisphosphate
- ATP - citrate
more on F26BP:
- F6P converted to F26BP when PFK-2 is dephosphorylated (so when insulin is acting) –> F26BP stimulates PFK1….and F6P is converted to F16P
ATP producing steps
1,3-BPG –> 3-PG by phosphoglycerate kinase
phosphoenolpyruvate –> pyruvate by pyruvate kinase
+ F16BP
- ATP - alanine
pyruvate dehyrogenase
acetyl-coA, CO2, and NADH
activated by increased NAD/NADH+ ratio, ADP, and Ca2+
3 enzymes, 5 cofactors (B1,2,3,5, and lipoic acid)
- arsenic inhibits lipoic acid –> vomiting, rice-water stools, garlic breath, QT long
pyruvate dehydrogenase complex deficiency (XL)
- pyruvate to lactic acid (LDH) and alanine (ALT)
- treat with ketogenic diet (high fat, high lysine and leucine) - these aas will not be metabolized to lactate
pyruvate can go acetyl coA, lactate (and NAD+), alanine, and oxaloacetate
- lactate - RBCs/WBCs, kidney medulla, lens, testes, cornea
- alanine - requires B6, ala carries amino groups from muscle to liver
- pyruvate + CO2 –> oxaloacetate, in mito, by pyruvate carboxylase + B7
- irreversible reaction - used in gluconeogenesis
TCA and ETC
TCA:
citrate is krebs starting substrate for making oxaloacetate
- a-ketoglutarate dehydrogenase ~ pyruvate dehydrogenase
- isocitrate dehydrogenase = RLS
isocitrate dehydrogenase, a-ketoglutarate dehydrogenase, and malate dehydrogaenase produce NADH
succinyl-coA synthetase (which turns succinyl-coA into succinate) - produces GTP
…10 ATP/acetyl coA
ETC: 1 NADH –> 2.5 ATP, 1 FADH2 –> 1.5 ATP
- malate-aspartate shuttle (heart and liver), glycerol-3-P shuttle (muscle)
- NADH to complex 1, FADH to complex 2 (aka succinate dehydrogenase)
- 2,4-dinitrophenol, ASA, thermogenin uncouple membrane
- rotenone inhibits complex 1 = pesticide
- antimycin A inhibits complex 3
- cyanide and CO - complex 4
- oligomycin inhibits ATP synthase
activated carriers
CoA, lipomide - acyl groups
TPP - aldehydes
gluconeogenesis
irreversible, occur in liver (muscle lacks glucose-6-phosphatase so cant participate in gluconeogenesis)
pyruvate carboxylase - B7, ATP, activated by acetyl-coA, in mitochondria
phosphoenolpyruvate carboxykinase - oxaloacetate to phosphoenolpyruvate, requires GTP, in cytosol
fructose-1,6-bisphosphatase (RLS) - F16P to F1P (F16P can also be converted from DHAP + glyceraldehyde-3P)
+ citrate - AMP - F26BP
glucose-6-phosphatase in ER - glucose-6-P to glucose
odd chain FAs enter TCA as succinyl coA and can undergo gluconeogenesis
- even chain FAs cant produce new glucose - they produce acetyl coA
HMP shunt
oxidative - glucose-6-P –> 2NADPH and ribulose-5-P
- NADPH used in reductive reactions
- glucose-6-P dehydrogenase (RLS) - deficiency (XR) + stressor (infection, exogenous oxidants) –> hemolytic anemia
- Heinz bodies = denatured Hb
- Bite cells - splenic macrophages try to remove Heinz bodies
non-oxidative (reversible) - ribulose-5-P to ribose, etc. by transketolases
CF
AR, C7, commonly del of Phe508 –> misfolded protein –> protein is retained in RER and not transported to cell membrane
- increased intracellular Cl- (in lungs and GI tract) - compensatory Na and H2O reabsorption
- more negative transepithelial potential - due to Na reabsorption
- can present with contraction alkalosis and loop diuretic like effects (K+ and H+ wasting)
- increased immunoreactive trypsinogen = newborn screening
complications:
- S aureus (infancy), P aeruginosa (adolescents), bronchitis and bronchiectasis –> reticulonodular pattern on CXR
- … biliary cirrhosis, liver disease, meconium ileus in newborns (aka bowel obstruction)
treat
- albuterol, aero dornase alfa (DNAse), hypertonic saline
- azithro
- ibu slows dz progression
- etc.
MD
Duchenne (XL) - frameshift or nonsense mutations (largest gene, increased chance of mutations) –> absent dystrophin –> progressive myofiber damage/necrosis
- dystrophin anchors actin to membrane proteins - which are then connected to ECM
- increased CK and aldolase
- pelvic girdle weakness and moves up
- onset before 5 yo
- dilated cardiomyopathy is the most common cause of death
Becker - deletions (non-frameshift) –> partial function
- later onset
Myotonic type 1 (AD) = CTG repeat in DMPK gene –> abnormal expression for myotonin protein kinase
- ….testicular atrophy, arrhythmia
trisomies
meiotic nondisjunction in women over 35 (»>robertsonian translocation)
21: flat facial profile, protruding tongue, small ears
- duodenal atresia, Hirschsprung disease, AV septal defect (described as holosystolic murmur), Brushfield spots, AML/ALL
- first trimester - increased nuchal transparency and hypoplastic nasal bone, decreased serum PAPP-A, increased bHCG
- second trimester quad screen - decreased AFP and estriol, increased bHCG and inhibin A
death by age 1
18: rocker-bottom feet, overlapping toes
- first tri - PAPP-A and b-HCG decreased
- quad screen - all four decreased
13: midline defects (cleft palate, holoprosencephaly), polydacytyl, cutis aplasia (absence of epidermis on top of scalp), congenital heart disease
- first tri: decreased b-HCG and PAPP-A
other chromosomal disorders
Cri-du-chat: 5p (short arm deletion), microcephaly, ID, VSD
Williams syndrome - microdeletion of long arm of 7 (elastin gene deleted)
- elfin facies, ID, hypercalcemia (increased sensitivity to vitamin D), extreme friendliness with strangers and well developed verbal skills, CV problems
22q11: 3rd and 4th pouches
- DiGeorge
- Velocardiofacial syndrome - no thymic/parathyroid defects
ethanol
side note: catalase turns H2O2 into H2O
- glutathione is like catalase - converts H2O2 to water
NAD+ is limiting reagent (used in dehydrogenase reactions) - alcoholics have high NADH/NAD+ ratio
- pyruvate to lactate
- oxalacetate to malate - prevents gluconeogenesis, also remember NAD+ is required for TCA
- DHAP –> glycerol-3-P –> fatty liver
- NADH inhibits FFA oxidation - disfavors TCA cycle (which makes NADH) –> acetyl-coA is used for ketogenesis
alcohol dehydrogenase = 0 order
metabolism sites
HUG - heme, urea, gluconeogenesis
cytosol - fatty acids/steroids, HMP shunt/nucleotides, proteins
mito - b-oxidation/ketogenesis, acetyl-coA/TCA/ETC
sorbitol
glucose, NADPH, aldose reductase–> sorbitol
sorbitol, NAD+, sorbitol dehydrogenase –> fructose
some tissues have mostly aldose reductase - lens, retina, kidneys, Schwann cells
lactase deficiency
rotavirus can cause loss of brush border
stool = low pH, breath - increased H2
urea cycle
ordinarily careless crappers are also frivolous about urination
RLS = NH3 + CO2, carbamoyl synthetase 1 –> carbamoyl phosphase
- N-acetylglutamate activates
carbamoyl phosphate enters urea cycle
aspartate contributes the last NH2 to urea
amino acids -NH3 = a-ketoacids
at the same time - a-ketoglutarate + NH3 = glutamate
- alanine transports ammonia from muscle to liver
renal ammoniagenesis: stimulated by acidosis
renal cells metabolize glutamine - NH3 –> glutamate - NH3 –> a-ketoglutarate - CO2 –> glucose
- end products are bicarb (reabsorbed to buffer acids in blood) and NH3 (excreted to trap acid in urine)
hyperammonemia
- slurring of speech, vomiting, asterixis, cerebral edema and blurred vision
- excess NH3 depletes a-ketoglutarate –> TCA cant proceed
- limit protein in diet, lactulose to trap NH4+, antibiotics (rifaximin) to kill colonic ammoniagenic bacteria
- give benzoate, phenylacetate, or phenylbutryate - they will react with glycine/glutamine and be renally excreted
ornithine transcarbamylase def - most common, XR (other urea cycle enzyme def will be AR)
- OTC normally converts CP + ornithine –> citrulline
- * excess CP is converted to orotic acid* (pyrimidine synthesis) - evident within first few days of life
- increased orotic acid in blood and urine, decreased BUN
(v. s. orotic acidura - megaloblastic anemia)
tryptophan, BH4
tryptophan to niacin requires B2 and B6
BH4:
- phe –> tryosine –> dopa
- serotonin
- NO
B6 for almost all aa derivatives
amino acids and urine
AR
maple syrup urine disease (AR) - CNS defects, ID, death
- leucine is neurotoxic
alkaptonuria (AR) - deficiency of homogentisate oxidase –> tyrosine cant be degraded to fumarate
- homogentisic acid accumulates in CT, sclera, urine (black on exposure to air)
- homogentisic acid is toxic to cartilage –> arthralgias
homocystinura (AR)
met cystathionine –> cysteine
- cystahtionine synthase def - decrease methionine, increase cysteine/B6/B12/folate
- decreased affinity of cystathionine synthase for PLP (B6) - more B6 and cysteine
- methionine synthase def - increase methionine
- results: …osteoporosis, marfanoid habitus, ocular changes (down and in lens subluxation), ID
cystinuria (AR) - COLA transport defect (cysteine, ornithine, lysine, arg)
- hexagonal stones - treat with alkalinization and hydration
- CN nitroprusside test is diagnostic (cyanide will convert cystine to cysteine –> color change in urine)
glycogen
abundant in the liver shortly after a meal
insulin –> protein phosphatase –> removes phosphate from glycogen synthase –> glycogen made
- glucose –> glucose-6P –> glucose-1P –> UDP-glucose –> glycogen
glucagon, epi –> PKA –> glycogen phosphorylase kinase activated –> phosphorylates glycogen phosphorylase –> glycogen to glucose
- branches have 1,6 bonds
glycogenolysis
1) glycogen phosphorylase liberates G1P residues until 4 residues remain on a branch (limit dextrin)
2) 4-a-d-glucanotransferase moves 3 G1P molecules off branch onto linkaage
3) 1,6-glucosidase liberates last residue (that was on branch)
(1,4-glucosidase is in lysosomes)
1,4-glucosidase deficiency occurs in Pompe disease
- no hypoglycemia but cardiomyopathy and hypotonia
- glycogen acc in lysosomes
- cardiomegaly
Cori disease - affects the debranching enzymes
- abnormal glycogen with very short outer chains
- hepatomegaly and steatosis
- fasting hypoglycemia, lactic acidosis, hyperuricemia and HLD
McArdle disease
- muscle phosphorylase deficiency - cant liberate G1P from muscle glycogen
- weakness but no rise in blood lactate after exercise, rhabdo
- treat by taking oral glucose prior to exercise
fatty acid metabolism
synthesis
1) citrate in mito –> citrate shuttle to cytoplasm
2) acetyl coA –> malonyl coA –> palmitate
degradation (carnitine for carnage)
1) (long chain) FA + coA –> fatty acyl-coA, inhibited by malonyl coA
2) carnitine shuttle sends this into the mito - fatty acyl coA –> acetyl coA –> ketone bodies and TCA
systemic primary carnitine def - LCFAs acc cell (they cant be shuttled into mito)
- defect in protein that imports carnitine into cells
- weakens, hypotonia, hypoketotic hypoglycemia, elevated muscle TGs
medium chain acyl-coA dehydrogenase def - accumulation of FA-carnitines in blood with hypoketotic hypoglycemia
- vomiting, lethargy, seizures, coma, liver dysfucntion
- can lead to sudden death in infants or kids
- avoid fasting
ketone bodies: made in liver, can be used by brain and muscle
- prolonged starvation and DKA - oxaloacetate is depleted for gluconeogenesis….buildup of acetyl coA –> ketone bodies
- in alcohols - NADH shunts oxaloacetate to malate –> acetyl coA again
- urine ketones doesnt detect b-hydroxybutyrate
fuel use
fed - glycolysis and aerobic respiration
fasting (between meals) - hepatic glycogenolysis, hepatic gluconeogenesis, adipose release of FFA
save glucose for RBCs (no mito, cant use ketones)
starvation 1-3 d
- hepatic glycogenolysis - deplete after 1 day
- adipose release of FFA, muscle and liver start using FFAs for energy
- hepatic gluconeogenesis - lactate, alanine, glycerol, propionyl-coA
starvation 3d+
1) adipose
2) protein –> organ failure and death
lipid transport
intestine –> chylomicrons –> chylomicron remnants –> uptaken by remnant receptors on liver
VLDL (released by liver) –> lipoprotein lipase turns it into IDL –> hepatic lipase degrades TGs leaving LDL
- IDL and LDL uptaken by LDL receptors on liver
- LDL taken up by peripheral tissues
lipoprotein lipase - on vascular endothelium, degrades TGs in chylomicrons and VLDL (released by liver)
hormone-sensitive lipase - degrades TGs stored in adipocytes
liver and intesine –> nascent HDL –> LCAT catalyzes esterification of 2/3 of plasma cholesterol –> mature HDL –> CETP mediates transfer of cholesterol esters to VLDL, IDL, and LDL
……..
apolipoproteins:
E - mediates remnant uptake, everything except LDL
A1 - activates LCAT (chylomicron, HDL)
C2 - lipoprotein lipase cofactor that catalyzes cleavage (chylomicron, VLDL, HDL)
B48 - mediates chylomicron secretion into lymphatics
B100 - binds to LDL receptor (VLDL, IDL, LDL)
lipoproteins:
cholesterol - cell membrane, bile acids, steroids, vitamin D
chylomicron - TGs to peripheral tissues, remnant delivers cholesterol to liver (cholesterol has been depleted)
VLDL - hepatic TGs to tissues
IDL - delivers TGs and cholesterol back to liver
LDL - delivers cholesterol to periphery, taken up by target cells by receptor-mediated endocytosis
HDL - transports cholesterol from periphery to liver, repository for C and E, secreted from liver and intestine, increased in alcoholics
abetalipoproteinemia - AR, ApoB48 and B100 def
- chylomicrons, VLDL, and LDL absent
- affected infants present with fat malabsorption, failure to thrive
- later signs: retinitis pigmentosa, vitamin E def, acanthocytosis
- treat with restriction of long chain FAs and vitamin E
familial dyslipidemias
1) hyperchylomicronemia - AR
- LPL or apoC2 def
- increased chylomicrons, TGs, cholesterol
- … HSM, eruptive/pruitic xanthomas, but NO increased risk for atherosclerosis
- creamy layer in supernatant
2) familial hypercholesterolemia - AD (homozygous form will present in childhood/adolescence)
- no LDL receptors
- 2a - LDL, cholesterol increased. 2b - VLDL also increased
….
3) dysbetalipoproteinemia - AR
- defective apoE –> chylomicrons and VLDL increased in blood
- premature atherosclerosis, tuberoeruptive xanthomas, xanthoma striatum palmare
4) hyperTG - AD - hepatic overproduction of VLDL
- increased VLDL and TGs (>1000 mg/dl) in blood
disorders of fructose metabolism
essential fructosuria (AR) - benign
- deficient fructokinase - fructose cant be converted to F1P
- hexokinase is upregulated - converts fructose into F6P –> enters glycolysis or glycogen synthesis
hereditary fructose intolerance
- deficient aldolase b - F1P cant be converted to DHAP/glyceraldehyde
- F1P is toxic –> hypoglycemia and vomiting after fructose ingestion
- hypoglycemia because F1P accumulates and depletes phosphate - inhibits glycogenolysis and gluconeogenesis
- failure to thrive, liver and renal failure
hemoglobins
initial Hb in a fetus = Gower Hb - z2e2, produced in embryonic yolk sac
- in a few weeks - fetal liver starts synthesizing HbF
in beta thalassemia - a2 chains precipitate –> premature lysis of RBCs
Hb electrophoresis - governed by charge
- HbA is negatively charged
- HbS - glutamate (negatively charged) replaced by valine (NP)
- HbC - glutamate replaced by lysine (positively charged)
- HbH migrates further than HbA
- overall on a gel: negative - HbC - Hb S - Hb A - HbH - positive
calories
1 g protein/carbs = 4 cal
1 g ethanol = 7 cal
1 g fat = 9 cal
glutathione
glutamate, glycine, cysteine
Fabry
XR - a-galactosidase deficiency –> ceramide trihexoside aka globotriaosylceramide acc
cataracts, parasthesias of hands and feet, angiokeratomas (~mole)
von Gierke diease
deficiency of glucose-6-phosphate - cant turn G6P into glucose
hypoglycemia, lactic acidosis, HM, H-TGs
macular red spots
Tay Sachs
- hexosaminidase A deficiency (GM2 ganglioside accumulates)
- cherry-red spots, loss of motor skills
- NO HSM
Niemann-Pick (AR)- sphingomyelinase def
- sphingomyelin accumulates in cells - lipid-laden foam cells in liver and spleen
- HSM, motor neuropathy and neuro regression, anemia, cherry red spots
- infantile type will lead to death by 3 years
aspartate
aspartate and alanine are gluconeogenic
Krabbe disease
galactocerebrosidase, galactocerebroside and psychosine accumulate
- infants have developmental delay, regression, hypotonia
- optic atrophy, seizures
Gaucher
AR - b-glucocerebrosidase accumulates
- HSM, pancytopenia, skeletal problems
G proteins
transmembrane domain - NP alpha-helxi
ligand binds - GDP is exchanged for GTP by a-unit –> a-unit dissociates
Gq - phospholipase C –> IP3 (Ca2+ from ER) and DAG
- DAG and Ca2+ activate PKC
insulin-mediated transport
via GLUT4 - only in muscle cells and adipocytes
all other cells perform insulin-ind transport
- GLUT1 - RBCs, BBB
- GLUT2 (bidirectional) - hepatocytes, b-cells, BL renal tubules, SI mucosa (think glucose-level ind effects)
GLUT3 - placenta and neurons
GLUT5 - fructose
deficiency of glycolytic enzymes
hexokinase and pyruvate kinase –> hemolytic anemia due to lack of ATP production
starch
~ glycogen
amylose, amylopectin
disaccharides
glucose + glucose = maltose
glucose + fructose = sucrose
glucose + galactose = lactose
orotic aciduria
AR - defect in UMP synthase
physical and mental retardation, megaloblastic anemia, elevated urinary orotic acid levels
treat with uridine supplementation - bypasses enzymatic defect,
metabolic syndrome
elevated TGs, low HDL cholesterol, central obesity
HTN
elevated glucose
PPAR family involved in pathogenesis
