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Biochem Flashcards

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
Q

pyruvate dehyrogenase

A

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
Q

TCA and ETC

A

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
Q

activated carriers

A

CoA, lipomide - acyl groups

TPP - aldehydes

28
Q

gluconeogenesis

A

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
Q

HMP shunt

A

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
Q

CF

A

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
Q

MD

A

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
Q

trisomies

A

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
Q

other chromosomal disorders

A

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
Q

ethanol

A

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
Q

metabolism sites

A

HUG - heme, urea, gluconeogenesis

cytosol - fatty acids/steroids, HMP shunt/nucleotides, proteins

mito - b-oxidation/ketogenesis, acetyl-coA/TCA/ETC

36
Q

sorbitol

A

glucose, NADPH, aldose reductase–> sorbitol

sorbitol, NAD+, sorbitol dehydrogenase –> fructose

some tissues have mostly aldose reductase - lens, retina, kidneys, Schwann cells

37
Q

lactase deficiency

A

rotavirus can cause loss of brush border

stool = low pH, breath - increased H2

38
Q

urea cycle

A

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
Q

tryptophan, BH4

A

tryptophan to niacin requires B2 and B6

BH4:

  • phe –> tryosine –> dopa
  • serotonin
  • NO

B6 for almost all aa derivatives

40
Q

amino acids and urine

A

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
Q

glycogen

A

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
Q

fatty acid metabolism

A

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
Q

fuel use

A

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
Q

lipid transport

A

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
45
Q

familial dyslipidemias

A

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

46
Q

disorders of fructose metabolism

A

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
47
Q

hemoglobins

A

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
48
Q

calories

A

1 g protein/carbs = 4 cal
1 g ethanol = 7 cal
1 g fat = 9 cal

49
Q

glutathione

A

glutamate, glycine, cysteine

50
Q

Fabry

A

XR - a-galactosidase deficiency –> ceramide trihexoside aka globotriaosylceramide acc

cataracts, parasthesias of hands and feet, angiokeratomas (~mole)

51
Q

von Gierke diease

A

deficiency of glucose-6-phosphate - cant turn G6P into glucose

hypoglycemia, lactic acidosis, HM, H-TGs

52
Q

macular red spots

A

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
53
Q

aspartate

A

aspartate and alanine are gluconeogenic

54
Q

Krabbe disease

A

galactocerebrosidase, galactocerebroside and psychosine accumulate

  • infants have developmental delay, regression, hypotonia
  • optic atrophy, seizures
55
Q

Gaucher

A

AR - b-glucocerebrosidase accumulates

- HSM, pancytopenia, skeletal problems

56
Q

G proteins

A

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

57
Q

insulin-mediated transport

A

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

58
Q

deficiency of glycolytic enzymes

A

hexokinase and pyruvate kinase –> hemolytic anemia due to lack of ATP production

59
Q

starch

A

~ glycogen

amylose, amylopectin

60
Q

disaccharides

A

glucose + glucose = maltose

glucose + fructose = sucrose

glucose + galactose = lactose

61
Q

orotic aciduria

A

AR - defect in UMP synthase

physical and mental retardation, megaloblastic anemia, elevated urinary orotic acid levels

treat with uridine supplementation - bypasses enzymatic defect,

62
Q

metabolic syndrome

A

elevated TGs, low HDL cholesterol, central obesity

HTN

elevated glucose

PPAR family involved in pathogenesis

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