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Biochem Flashcards

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1
Q

DNA

A

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

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2
Q

De novo purine and pyrimidine synthesis

A

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

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3
Q

purine salvage

A

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
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4
Q

DNA replication

A

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

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5
Q

mutations in DNA

A

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

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6
Q

lac operon

A

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

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7
Q

RNA

A

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

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8
Q

tRNA

A

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

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9
Q

protein synthesis

A

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

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10
Q

cell cycle

A

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

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11
Q

Golgi

A

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)

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12
Q

fatty acids

A

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
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13
Q

cytoskeleton

A

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.

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14
Q

NA/K ATPase

A

pump+P = 3 Na leave
pump dephosphorylated = 2K in
ouabain inhibits binding to K+ site - cardiac glycoside, toxin

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15
Q

collagen

A

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
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16
Q

elastin

A

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)

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17
Q

DNA IDs

A

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

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18
Q

genetics vocab

A

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
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19
Q

XD

A

hypophosphatemic (vitamin D resistant) rickets, fragile X, Alport

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20
Q

AD

A

…familial adenomatous polyposis, familial hypercholesterolemia, hereditary hemorrhagic telangiectasia

Li Fraumeni, MENs, NF1&2, TS, VHL

Huntington

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21
Q

AR

A

albinism, CF, glycogen storage diseases, Hurler, hemochromatosis, PKU, sphingolipidoses (except Fabry), Wilsons disease

thalassemias, Kartageners

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22
Q

XR

A

ornithine transcarbamylase def, Lesch-Nyhan

Fabry, Hunter, ocular albinism

Wiskott-Aldrich, Bruton agammaglobulinemia

hemophilia

DMD, BMD

lyonization - due to bar bodies

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23
Q

phosphorylase

A
  • lase adds things

adds P without using ATP

synthetase - reaction using no energy source

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24
Q

glycolysis

A

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

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25
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
26
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
27
activated carriers
CoA, lipomide - acyl groups | TPP - aldehydes
28
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
29
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
30
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.
31
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
32
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
33
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
34
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
35
metabolism sites
HUG - heme, urea, gluconeogenesis cytosol - fatty acids/steroids, HMP shunt/nucleotides, proteins mito - b-oxidation/ketogenesis, acetyl-coA/TCA/ETC
36
sorbitol
glucose, NADPH, aldose reductase--> sorbitol sorbitol, NAD+, sorbitol dehydrogenase --> fructose some tissues have mostly aldose reductase - lens, retina, kidneys, Schwann cells
37
lactase deficiency
rotavirus can cause loss of brush border stool = low pH, breath - increased H2
38
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)
39
tryptophan, BH4
tryptophan to niacin requires B2 and B6 BH4: - phe --> tryosine --> dopa - serotonin - NO B6 for almost all aa derivatives
40
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)
41
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
42
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
43
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
44
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
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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
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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
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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
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calories
1 g protein/carbs = 4 cal 1 g ethanol = 7 cal 1 g fat = 9 cal
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glutathione
glutamate, glycine, cysteine
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Fabry
XR - a-galactosidase deficiency --> ceramide trihexoside aka globotriaosylceramide acc cataracts, parasthesias of hands and feet, angiokeratomas (~mole)
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von Gierke diease
deficiency of glucose-6-phosphate - cant turn G6P into glucose hypoglycemia, lactic acidosis, HM, H-TGs
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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
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aspartate
aspartate and alanine are gluconeogenic
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Krabbe disease
galactocerebrosidase, galactocerebroside and psychosine accumulate - infants have developmental delay, regression, hypotonia - optic atrophy, seizures
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Gaucher
AR - b-glucocerebrosidase accumulates | - HSM, pancytopenia, skeletal problems
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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
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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
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deficiency of glycolytic enzymes
hexokinase and pyruvate kinase --> hemolytic anemia due to lack of ATP production
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starch
~ glycogen amylose, amylopectin
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disaccharides
glucose + glucose = maltose glucose + fructose = sucrose glucose + galactose = lactose
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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,
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metabolic syndrome
elevated TGs, low HDL cholesterol, central obesity HTN elevated glucose PPAR family involved in pathogenesis

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