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Biochemistry > Metabolism > Flashcards

Metabolism Flashcards

0
Q

Mitochondria metabolism

A

Fatty acid oxidation (B-oxid), acetyl-CoA production, TCA cycle, oxidative phosphorylation

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1
Q

Metabolism sites

A

Mitochondria
Cytoplasm
Both

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2
Q

Cytoplasm metabolism

A

Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis

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3
Q

Both

A

Heme synthesis, Urea cycle, Gluconeogenesis

“HUGs take two (both)”

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4
Q

Enzyme terminology

A

Enzyme name describes fxn

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5
Q

Kinase

A

Uses ATP to add high-energy phosphate to substrate

- Phosphofructokinase

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6
Q

Phosphorylase

A

Adds inorganic phosphate onto substrate without ATP (glycogen phosphorylase)

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7
Q

Phosphatase

A

Removes phosphate group from substrate

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8
Q

Dehydrogenase

A

Catalyses oxidation-reduction rxn

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9
Q

Hydroxylase

A

Adds hydroxyl group (-OH) to substrate

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10
Q

Carboxylase

A

Transfers CO2 groups with help of biotin

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11
Q

Mutase

A

Relocates fxnal group within molecule

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12
Q

Rate limiting step of glycolysis

A

Phosphofructokinase (PFK-1)

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13
Q

Rate limiting step of gluconeogenesis

A

Fructose-1,6-bisphsphatase

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14
Q

Rate limiting step of TCA cycle

A

Isocitrate dehydrogenase

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15
Q

Rate limiting step of Glycogenesis

A

Glycogen synthase

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16
Q

Rate limiting step of Glycogenolysis

A

Glycogen phosphorylase

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17
Q

Rate limiting step of HMP shunt

A

Glucose-6-phosphate dehydrogenase (G6PD)

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18
Q

Rate limiting step of de novo pyrimidine synthesis

A

Carbomoyl phosphage synthetase II

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19
Q

Rate limiting step of de novo purine synthesis

A

Glutamine-phosphoribosylpyrophospage (PRPP) amidotransferase

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20
Q

Rate limiting step of urea cycle

A

Carbomyl phosphate synthetase I

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21
Q

Rate limiting step of Fatty acid synthesis

A

Acetyl-CoA carboxylase (ACC)

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22
Q

Rate limiting step of Fatty acid oxidation

A

Carnitine acyltransferase I

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23
Q

Rate limiting step of Ketogenesis

A

HMG-CoA synthase

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24
Q

Rate limiting step of cholesterol synthesis

A

HMG-CoA reductase

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25
Q

ATP production

A

Aerobic metabolism of glucose:

  • 32 ATP via malate-aspartate shuttle (heart + liver)
  • 30 ATP via glycerol-3-phosphate shuttle (muscle)

Anaerobic glycolysis:
- 2 ATP per glucose

ATP hydrolysis - can be coupled to unfavorable rxns

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26
Q

ATP carrier molecule

A

phophoryl groups

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27
Q

NADH, NADPH, FADH2 carrier molecule

A

Electrons

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28
Q

CoA and lipoamide carrier molecules

A

Acyl groups

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29
Q

Biotin carrier molecules

A

CO2

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30
Q

Tetrahydrofolates carrier molecules

A

1-C units

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31
Q

SAM carrier molecules

A

CH3 groups

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32
Q

TPP carrier molecules

A

Aldehydes

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33
Q

Universal electron acceptors

A

Nicotinamides (NAD+ from Vit B3, NADP+) and flavin molecules (FAD+ from VitB2)

  • NAD+ used in catabolic processes, carry reducing equiv away as NADH
  • NADPH used in anabolic processes (steroid/FAs synthesis) to supply reducing equiv
  • NADPH - product of HMP shunt; used in: anabolic processes, respiratory burst, cytochrome p450, glutathione reductase
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34
Q

Glucose –> glucose-6-P via hexokinase vs. glucokinase

A

Hexokinase: All tissues except liver + B-cells of pancreas

  • Not induced by insulin
  • Feedback inhibited by G-6-P
  • Mutation not assoc w/ maturity-onset diabetes of young (MODY)
  • *Low [glucose] - hexokinase sequesters glucose in tissue

Glucokinase: Only liver and B-cells of pancreas

  • Induced by insulin
  • No feedback inhibition by G-6-P
  • Mutation assoc w/ maturity-onset diabetes of young (MODY)
  • *High [glucose] - glucokinase stores excess in liver
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35
Q

Glycolysis regulation

A

Glucose + 2Pi + 2ADP + 2NAD+ –> 2 pyruvate + 2ATP + 2NADH + 2H+ + 2H2O

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36
Q

Parts of glycolysis rxn needing ATP

A
  • Glucose –> Glucose-6-P (via hexokinase or glucokinase)
  • G6P inhibits hexokinase
  • F6P inhibits glucokinase
  • Fructose-6-P –> Fructose 1,6 BP (via phosphofructokinase-1) = Rate limiting
  • Inhibited by ATP and citrate
  • Activated by AMP and fructose-2,6-BP
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37
Q

Parts of glycolysis rxn producing ATP

A

1,3-BPG –> 3-PG (via phosphoglycerate kinase)

Phosphoenolpyruvate –> pyruvate (via pyruvate kinase)

  • Inhibited by ATP, alanine
  • Acitvated by fructose-1,6-BP
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38
Q

Gluconeogenesis

A

F 1,6BP –> F-6-P (via fructose bisphosphatase 1 = F1,6BPase)

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39
Q

Regulation of glycolysis vs. gluconeogenesis via F-2,6BP

A

F2,6BP = fructose 2,6 bisphosphate –> intermediate between F-6-P and F-1,6BP
Balance of F2,6BPase and PFK2

  • Fed: PFK-2 (activates phosphofructokinase-1)
    [low glucagon, low cAMP, low protein kinase A, low F2,6BPase/high PFK2 = more glycolysis, less gluconeogenesis]
  • Fasting: F2,6BPase (activates fructose bisphophatase 1)
    [high glucagon, high cAMP, high protein kinase A, high F2,6BPase/low PFK2 = less glycolysis, more gluconeogenesis]

*FBPase-2 and PFK2 are same bifxnal enzyme w/ fxnal reversal by phosphorylating protein kinase A

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40
Q

Pyruvate dehydrogenase complex

A

Mitochondrial enzyme complex –> links glycolysis to TCA cycle!
- Regulated differently in fasting vs. fed states (active in fed, inactive fasting)

*Similar to a-ketoglutarate dehydrogenase (converts a-ketoglutarate to succinyl CoA)

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41
Q

Pyruvate dehydrogenase rxn

A

Pyruvate + NAD+ + CoA –> acetylCoA + CO2 + NADH

Activated by exercise, increases:

  • NAD+/NADH ratio
  • ADP
  • Ca+2
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42
Q

Pyruvate dehydrogenase deficiency

A

Pyruvate builds up –> shunted to lactate (via LDH) or alanine (via ALT)

  • Sx - neuro defects, lactic acidosis, high [alanine] as infant
  • Tx: incr intake of ketogenic nutrients (lysine/leucine)
  • “Lycine and leucine = onLy pureLy ketogenic AAs”
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43
Q

Pyruvate metabolism

A

4 Pyruvate pathways:

  • AcetylCoA: pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid)
  • Goes into TCA cycle
  • Oxaloacetate: pyruvate carboxylase (biotin)
  • Replenishes TCA cycle
  • Alanine: alanine aminotransferase = ALT (B6)
  • Lactic acid: lactic acid dehydrogenase = LAD (B3)
  • Pathway for RBCs, leukocytes, kidney medulla, lens, testes, cornea
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44
Q

TCA Cycle = Krebs cycle

A

Pyruvate –> acetyl CoA makes 1NADH, 1CO2

  • TCA makes 3NADH, 1FADH2, 2CO2, 1GTP = 10 ATP/acetyl-CoA
  • Occurs in mitochondria (ATP made in mitochondria)

Citrate, isocitrate, a-ketoglutarate, succinylCoA, succinate, fumarate, malate, oxaloacetate
- “Citrate Is Kreb’s Starting Substrate For Making Oxaloacetate”

Enzymes: citrate synthase, isocitrate dehydrogenase, a-ketoglutarate dehydrogenase

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45
Q

Electron transport chain

A

Electrons transfer via redox rxns, H+ travel with electrons

  • NADH e- come into mitochondria (malate-aspartate or glycerol-3-p shuttle)
  • Creates proton gradient. Proton gradient + oxidative phosphorylation = production of ATP
  • Final electron acceptor = O2
  • *Inner mitochondrial membrane:
  • Complex 1, Complex II, CoQ, Complex III, cytochrome C, complex IV, complex V
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46
Q

ATP made w/ ATP synthase

A

1 NADH –> 2.5 ATP

1 FADH –> 1.5 ATP

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47
Q

Poisons of oxidative phosphorylation

A
  • Electron transport inhibitors
  • ATP synthase inhibitors
  • Uncoupling agents
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48
Q

Electron transport inhibitors

A

Directly inhibit electron transport –> get decreased proton gradient, blocks ATP synthesis
- Rotenone, cyanide, antimycin A, CO

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49
Q

ATP synthase inhibitors

A

Directly inhibit mitochondrial ATP synthase –> incr proton gradient

  • No ATP made bc electron transport stops
  • Oligomycin
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50
Q

Uncoupling agents

A

Incr membrane permeability –> decr proton gradient and incr O2 consumed

  • ATP production stops, electron transport continues (makes heat)
  • 2,4-Dinitrophenol (wt loss), aspirin (fever w/ aspirin OD), thermogenin in brown fat
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51
Q

Gluconeogenesis

A
  • In liver - maintains euglycemia in fasting
  • Muscle can’t participate bc doesn’t have glucose-6-phosphatase
  • Odd-chain fatty acids - make propionylCoA, can enter TCA cycle as succinyl CoA, and undergo gluconeogenesis
  • Even-chain can’t (only make acetylCoA equiv)
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52
Q

Irreversible enzymes of gluconeogenesis

A
  • Pyruvate carboxylase: pyruvate –> oxaloacetate
  • In mitochondria; requires ATP/biotin; activated by Acetyl-CoA
  • Phosphoenolpyruvate carboxykinase: oxaloacetate to phosphoenolpyruvate (PEP)
  • In cytosol; requires GTP
  • Fructose 1,6 Bisphosphatase: F1,6BP –> F-6-P
  • In cytosol; citrate activates, F2,6BP inhibits
  • Glucose-6-phosphatase: G6P –> glucose
  • In ER

**Deficiency in enzymes causes hypoglycemia bc can’t do gluconeogenesis

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53
Q

Oxidative reaction of HMP shunt

A

Irreversible:

  • G-6-P –> 2NADPH + Ribulose-5P
  • Via G6PD; NADPH inhibits G6PD
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54
Q

HMP shunt

A

Pentose phosphate pathway:

  • Makes NADPH (reducing agent) and ribose
  • NADPH creates reducing intracellular environment; **Not used to generate ATP!
  • High NADPH will inhibit this
  • *Need this for FA and cholesterol synthesis (anabolic)
  • Oxidative + nonoxidative phases
55
Q

Nonoxidative reaction of HMP shunt

A

Reversible:

  • Ribulose 5P Ribose 5P, G3P, F6P
  • Via phosphopentose isomerase or transketolases
56
Q

Respiratory burst (oxidative burst)

A

Activation of phagocyte NADPH-oxidase complex (neutrophils/monocytes) –> uses O2 as substrate
- Important role in immune response (rapid release of ROS)
- O2 –> O2- –> H2O2 –> HOCl (bleach)
(O2 to O2- with NADPH and NADPH oxidase)

57
Q

Enzymes of oxidative burst of phagolyosome

A
  • O2 –> O2 - via NADPH oxidase
  • O2 –> H2O2 via SOD (superoxide dismutase)
  • H2O2 –> HOCl (bleach) via MPO (myeloperoxidase)
  • NADPH oxidase - plays role in creating + neutralizing ROS
  • Myeloperoxidase has blue-green heme pigment –> sputum
58
Q

Chronic granulomatous disease and oxidative burst

A
  • *Defect in NADPH oxidase Immune cells can’t make ROS well
  • Can use H2O2 from invading organisms + convert to ROS
  • But at incr risk of infection from catalase + species (S. aureus, aspergillus) which catalyze own H2O2; phagocytes don’t have ROS to fight infection

*Screen = Nitroblue tetrazolium test (NBT) - tests for NADPH oxidase activity

59
Q

Myeloperoxidase deficiency

A

MPO deficiency

  • Can’t convert H2O2 to bleach
  • Incr candida infections
  • NBT normal (bc NADPH intact; MPO not intact)
60
Q

P. aeruginosa and ROS

A

Pyocyanin of P. aeruginosa makes ROS to kill competitive microbes

61
Q

Lactoferrin

A

Found in secretory fluids/neutrophils, inhibits microbial growth via iron chelation

62
Q

G6PD deficiency presentation

A

X-linked recessive, most common enzyme deficiency
- More in blacks, more malaria resistance

Blood smear: Heinz bodies = oxidized Hgb in RBCs; Bite cells = phagocytic removal of Heinz by splenic macrophages
- “Bite into some Heinz ketchup”

63
Q

G6PD deficiency pathophys

A
  • Need NADPH to keep glutathione reduced (detoxes free radicals/peroxides; H2O2 to H2O)
  • Decr NADPH in RBC = hemolytic anemia bc poor RBC defense against:
    1) oxidizing agents - fava beans, sulfonamides, primaquine, anti-TB
    2) infection - free radicals in inflamm response go into RBC, cause oxidative damage

*Defic affects cholesterol and FA synthesis

65
Q

D/o of fructose metabolism

A

More benign than d/o of galatose metabolism

  • Essential fructosuria - benign
  • Fructose intolerance
66
Q

Essential fructosuria

A

AR, Defect in fructokinase

  • Benign, asymptomatic bc fructose not trapped in cells
  • Sx: fructose in blood/urine

*Dipstick neg (specific to glucose), reducing sugar in urine

67
Q

Fructose intolerance

A

AR, deficiency in aldolase B

  • Fructose-1-P accumulates, decr available phosphate, inhibits gluconeogenesis or glucogenolysis
  • Sxs - hypoglycemia, jaundice, cirrhosis, vomiting (after eating juice, honey, fruit)
  • Dx - dipstick neg (specific to glucose), reducing sugar in urine
  • Tx - decr fructose and sucrose (glucose + fructose)
68
Q

D/o of galactose metabolism

A
  • Galactokinase deficiency (infantile cataracts)
  • Classic galatosemia (liver, brain and cataracts; more severe)

*Dipstick neg (specific to glucose), reducing sugar in urine

68
Q

Classic galactosemia

A

AR, absence of galactose-1-phosphate uridyltransferase

  • Toxic substances build up (galactitol in lens of eye)
  • Sx - FTT, jaundice, hepatomegaly, infantile cataracts, intellect disab
  • Tx - exclude galactose/lactose (galactose + glucose) from diet

*Can get E. coli sepsis in neonates

69
Q

Galactokinase deficiency

A

AR, hereditary galactokinase deficiency; mild

  • Galactose accumulates if in diet
  • Sx - galactose in blood/urine, infantile cataracts (can present as failure to track objects or have social smile)

*Dipstick neg (specific to glucose), reducing sugar in urine

70
Q

FAB GUT

A

Fructose is to adolase B, as Galactose is to UridylTransferase

71
Q

Sorbitol

A

Alcohol counterpart of glucose

  • Glucose trapped in cell can go to sorbitol (via aldose reductase)
  • Some tissues then convert sorbitol –> fructose (sorbitol dehydrogenase)
  • If lack enzyme, get sorbitol accumulation = osmotic damage
  • Cataracts, retinal problems, peripheral neuropathy w/ hyperglyc in DM
  • Liver, ovaries, seminal vesicles have aldose reductase + sorbitol dehydrogenase
  • Schwann cells, retina, kidneys only have aldose reductase (hence, damage in hyperglycemia of DM!)
72
Q

Lactase deficiency presentation

A

Sx: bloating, cramping, flatulence, osmotic diarrhea

Dx: Lactose tolerance test

  • Stool = low pH (acidic)
  • Breath = high hydrogen (acidic)
  • *Normal intestinal biopsy (if hereditary)

Tx:
- Avoid dairy or take lactase pills

73
Q

Lactase deficiency pathophys

A

Insufficient lactase enzyme = lactose intolerant

  • Lactase fxn on brush border to digest lactose into glucose/galactose; lactose is in human/cow milk
  • Lactase defic = lactose undigested –> osmotic substance, get incr H2O/electrolyte secretion
  • Primary = decline after childhood, worse w/ age
  • Secondary = loss of brush border from gastroenteritis (rota), autoimmune etc
  • Congenital = rare; defective gene
74
Q

Amino acids

A

Only L-form are in proteins

  • Essential - need supplementation in diet
  • Acidic
  • Basic
75
Q

Urea cycle

A

AA catabolism forms pyruvate/acetylCoA = metabolic fuel (feed into TCA as fumarate)
- NH3 converted to urea, excreted by kidney

“Ordinary Careless Crappers Are Also Frivolous About Urination”
- Ornithine, carbomyl phosphate, citrulline, aspartate, arginosuccinate, fumarate (TCA), arginine, urea

76
Q

Transporters of ammonia

A

Alanine and glutamate

  • Glutamate-NH3 in muscle, can’t cross to blood
  • Transfer to alanine-NH3, crosses blood (Cori cycle; uses a-ketoglutarate)
  • Then alanine transfers NH3 to glutamate present in liver
  • uses a-ketoglutarate (makes glutamate for NH3 to add to in liver)
77
Q

Hyperammonemia

A

Acquired (liver disease) or hereditary (urea cycle enzyme defic)

  • Excess NH4+, depletes a-ketoglutarate –> inhibits TCA cycle
  • Sx: tremor (asterixis), slurred speech, somnolence, vomiting, cerebral edema, blurred vision
  • Tx: limited protein intake, Benzoate/phenylbutyrate bind AA + excrete; Lactulose to acidify GI tract + trap NH4+ to excrete
78
Q

N-acetylglutamate deficiency

A

Cofactor for carbomyl phosphate synthetase 1 (CO2 + NH3 –> caromyl phosphate)

  • Deficiency = hyperammonemia
  • Same presentation of carbomyl phosphate synthetase 1 deficiency, but nl ornithine/urea cycle enzyme levels
79
Q

Ornithine transcarbamylase deficiency

A

Most common urea cycle d/o. X-linked recessive (other enzyme defic = AR)

  • Inhibits ammonia excretion, see in 1st days of life
  • Dx: incr orotic acid in blood/urine, low BUN, hyperammonemia sxs
  • *No megaloblastic anemia (See in orotic aciduria)
80
Q

Catecholamine synthesis/tyrosine catabolism

A

Phenylalanine –> Tyrosine –> DOPA (dihydroxyphentlalanine) –> DA –> NE –> Epi –> Metanephrine –> VMA

  • DA –> homovanillic acid
  • NE –> normetanephrine –> vanillylmandelic acid (VMA)
81
Q

Defects in catecholamine synthesis

A

Defects:

  • Phenylalanine to tyrosine = PKU
  • Phenylalanine hydroxylase
  • DOPA to melanin = albinism
  • Tyrosinase
82
Q

PKU presentation

A
  • Sx - intellectual disabibility, musty odor, light skin, eczema, sz
  • Dx - screen for 2-3 d after birth (have maternal enzymes)
  • Tx - decr phenylalanine and incr tyrosine in diet (avoid aspartate sweetener = phenylalanine)
83
Q

PKU = phenylketouria pathophys

A

AR, mutated gene for phenylalanine hydroxylase; can’t convert phenylalanine to tyrosine

  • Malign PKU = decr tetrhydrobiopterin cofactor (or dihydrobiopterin reductase enzyme) –> decr DA, high prolactin
  • Tyrosine = essential AA here (must eat)
84
Q

Maternal PKU

A

Lack of proper diet therapy in pregnancy

- Infants: microcephaly, intellectual disability, growth retardation, congenital heart defects

85
Q

Alkaptonuria

A

AR, ochronosis, deficiency in homogentisate oxidase (breakdown tyrosine to fumarate)

  • Benign
  • Sx - dark connective tissue, brown pig sclera, urine black when sits (oxidized), debilitating arthralgias (homogentisic acid toxic to cartilage)
86
Q

Cystinuria

A

AR, defect in renal PCT/intestinal AA transporter for COLA (cysteine, ornithine, lysine, arginine)

  • Cystine = 2 cysteines w/ disulfide bond
  • High urinary cystine - can get hexagonal cystine stones
  • Dx: urinary cyanide-nitroprusside test
  • Tx: alkalinize urine (Kcitrate, acetazolamide) and chelating agents (incr cystine stone solubility), hydration
87
Q

Homocystinuria

A

AR, multiple types - all result in excess homocysteine

  • Defect in cystathionine synthase or homocysteine methyltransferase
  • Dx: incr homocysteine in urine, intellectual disability, osteoporosis, tall stature, kyphosis, lens subluxation (down/in), thrombosis, atherosclerosis
  • High homocysteine = prothrombotic
88
Q

Maple syrup urine disease

A

AR, blocked degradation of branched ammino acids (isoleucine, leucine, valine)
- Due to decr a-ketoacid dehydrogenase (B1 cofactor)
- **Get high a-ketoacids in blood (esp leucine)
- Sx: urine smells like maple syrup/burnt sugar, severe CNS defects, intellectual disabil, death
- Tx: restrict leucine, isoleucine, valine in diet; thiamine (B1) supplement
“I Love Vermont maple syrup from trees (with branches)”

89
Q

Insulin production

A
  • Pre-proinsulin –> inserts into ER, cleave off “pre” part –> proinsulin (made into C-peptide and insulin)
  • Insulin a/B chains combine
90
Q

Homocysteine pathway

A

Methionine cystathionine –> cysteine

  • Methionine (via homocysteine methytransferase, B12, folate)
  • Cystathionine (via cystathionine synthase, B6, serine)
91
Q

Glycogen regulated by insulin and glucagon/epinephrine

A

Glucagon - GPCR, adenylyl cyclase, cAMP, protein kinase A
*Activates glycogen phosphorylase; PKA inhibits glycogen synthase

Insulin - TKI, phosphorylated, PI3 kinase, PIP3-PIP2
*Activates glycogen synthase, inhibits glycogen phosphorylase

92
Q

Glycogen structure

A 
Branches = a(1,6) bonds
Linkages = a(1,4) bonds
93
Q

Glycogen in skeletal muscle

A

Glycogenolysis:

  • Glycogen –> glucose-1-phosphate –> glucose-6-P
  • *Rapidly metabolized during exercise
94
Q

Glycogen in hepatocytes

A

Glycogen stored, get glycgenolysis to maintain appropriate glucose levels

  • Glycogen phosphorylase cleaves off G-1-P from branched glycogen until 4 before branch point
  • 4-a-D-glucanotransferase (debranching enzyme) moves 3 G-1-Ps from branch to linkage
  • a-1,6 glucosidase (debranching enzyme) cleaves last G-1-P on branch

*Small amount of glycogen degraded in lysosomes by acid maltase (a1,4-glucosidase)

95
Q

Glycogen storage diseases

A

12 types, abn glycogen metabolism + accumulation of glycogen in cells

  • “Very Poor Carbohydrate Metabolism”
  • Type 1: Von Gierke Disease
  • Type II: Pompe disease
  • Type III: Cori Disease
  • Type IV: McArdle disease
96
Q

Type I glycogen storage disease

A

AR, Von Gierke disease. Glucose-6-phosphatase deficiency

  • Severe fasting hypoglycemia, high liver glycogen, high blood lactate, hepatomegaly
  • Tx - oral glucose; avoid fructose/galactose
97
Q

Type III glycogen storage disease

A

AR, Cori disease. Debranching enzyme (a1,6-glucosidase)

- Milder version of Type I, nl blood lactate

98
Q

Type II glycogen storage disease

A

AR, Pompe disease. Lysosomal a1,4 glucosidase (acid a glucosidase = acid maltase)
- Cardiomyopathy, hepatomegaly, early death; “Pompe trashes Pump”

99
Q

Lysosomal storage diseases

A

Deficiency of lysosomal enzymes

- Get accumulation of abn metabolic products

100
Q

Type IV glycogen storage disease

A

AR, McArdle disease. Skeletal muscle glycogen phosphorylate defic.
- Incr glycogen in muscle (can’t break down = impaired energy generation). Painful muscle cramps, myoglobinuria w/ exercise, arrhythmias from electrolyte problems

101
Q

Fabry disease

A

X-linked recessive, deficient a-galactosidase A

  • Peripheral neuropathy of hands/feet, angiokeratomas, CV/renal disease
  • Accumulate ceramide trihexoside
102
Q

Gaucher disease

A

AR, most common lysosomal storage disease, glucocerebrosidase (B-glucosidase) defic

  • Hepatosplenomegaly, pancytopenia, avasc necrosis of femur, bone crises, Gaucher celss (macrophages w/ lipid, look like crumpled paper)
  • Tx: recombinant glucocerebrosidase
  • Accumulate glucocerebroside
103
Q

Niemann-Pick disease

A

AR, spingomyelinase defic

  • Progressive neurodegeneration, hepatosplenomegaly, “cherry-red” spot on macula, foam cells (lipid in macrophages)
  • Accumulate spingomyelin

“No man picks (Neimann-Pick) his nose with his sphinger (sphingomyelinase)”

104
Q

Tay-Sachs disease

A

AR, hexosaminidase A defic

  • Progressive neurodegeneration, dx delay, “chery red” spot on macula, lysosomes w/ onion skin; no hepatosplenomegaly (vs. Neimann-Pick)
  • Accumulate GM2 ganglioside

“Tay-SaX lacks heXosaminidase”

105
Q

Krabbe disease

A

AR, Galactocerebrosidease defic

  • Peripheral neuropathy, dx delay, optic atrophy, globoid cells
  • Accumulate galactocerebroside
106
Q

Metachromatic leukodystrophy

A

AR, arylsulfatase A defic

  • Central/periph demyelination w/ ataxia, dementia
  • Accumulate Cerebroside sulfate
107
Q

Hurler syndrome

A

AR, a-L-iduronidase defic

  • Dx delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
  • Accumulate heparan sulfate, dermatan sulfate
108
Q

Hunter syndrome

A

X-linked recessive, iduronate sulfate defic

  • Milder Hurler + aggressive bx, no corneal clouding
  • Accumulate heparan sulfate, dermatan sulfate

“Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-recessive)”

109
Q

Fatty Acid degradation

A
  • Requires carnitine shuttle for Acyl-CoA to get into mitochondrial matrix
  • FA + CoA –> Acyl-CoA –> carnitine shuttle –> Actl-CoA –> B-oxid to ketones/TCA cycle
110
Q

Fatty Acid synthesis

A
  • Requires citrate shuttle for citrate to get out of mitochondrial matrix
  • Citrate –> shuttle –> Acetyl-CoA –> FA synth
111
Q

Carnitine deficiency

A

Can’t transport LCFAs into mitochondria, get toxic accumulation
- Sx: weakness, hypotonia, hypoketotic hypoglycemia

112
Q

Acyl-CoA dehydrogenase

A

Used to break down Acyl-CoA into ketones and TCA

  • Deficiency = high dicarboxylic acids, low glucose/ketones
  • Acetyl-CoA regulates pyruvate carboxylase in gluconeogenesis; if Acetyl-CoA low, glucose low
113
Q

Ketone bodies

A

Liver: FAs and AAs broken down into acetoacetate and B-hydroxybutyrate (ketones) for muscle use
- Acetyl-CoA branches to TCA, FAs or ketones

114
Q

Causes of increased ketone bodies

A
  • Starvation/DKA - oxaloacetate used up for gluconeogenesis
  • Alcoholism - extra NADH shunts oxaloacetate to malate
  • Both get buildup of acetyl-CoA (can’t combine w/ oxaloacetate/enter TCA to make citrate)
  • This shunts glucose and FFAs to production of ketone bodies
115
Q

Testing for ketones

A
  • Breath smells like acetone (fruity)

- Urine test for ketones doesnt pick up B-hydroxybutyrate

116
Q

Energy (kcal) per type

A
  • Protein/carb = 4kcal
  • Fat = 9kcal
  • Alcohol = 7kcal
117
Q

Metabolic fuels use in exercise

A
  • Stored ATP - 2 s
  • Creatinine phosphate - 10s
  • Anaerobic metabolism - 1 min
  • Aerobic metabolism - >1 min
118
Q

Regulation in fasting/starvation states

A

*Main goal to supple glucose to brain and RBCs

119
Q

Fed state (after meal)

A

Glycolysis and aerobic respiration

*Insulin stimulates storage of lipids, proteins, glycogen

120
Q

Fasting state (btwn meals)

A

Hepatic glycogenolysis (major)
Hepatic glucogenolysis, adipose release of FFA (minor)
*Glucagon + adrenaline stimulate use of fuel reserves

121
Q

Starvation day 1-3

A

Blood glucose maintained by:

  • Hepatic glycogenolysis
  • Depleted after 1 day
  • Adipose release FFAs
  • Muscle/liver shift fuel use from glucose to FFA
  • Hepatic gluconeogenesis from periph lactate/alanine and adipose tissue

RBCs lack mitochondria, can’t use ketones

122
Q

Starvation after day 3

A

Adipose sotres - ketone bodies main source of energy for brain

  • After depleted, accelerates protein degradation - organ failure/death
  • More stores = longer survival time
123
Q

Cholesterol synthesis

A

Acetyl-CoA –> Acetoacetyl-CoA –> HMG-CoA –> Mevalonate –> cholesterol

  • Branch from HMG-CoA (can go to cholesterol or ketones)
  • HMG-CoA reductase = rate-limiting enzyme, induced by insulin

STATINS - competitively/reversibly inhibit HMG-CoA reductase!

124
Q

Statins and cholesterol synthesis

A

HMG-CoA reductase = rate-limiting enzyme

- Statins competitive/reversibly inhibit HMG-CoA reductase –> inhibits cholesterol synthesis

125
Q

Lipid transport enzymes

A
  • Pancreatic enzymes - degrade TG in small intestine –> chylomicrons
  • Lipoprotein Lipase (LPL) - degrades TG in chylomicrons + VLDLs
  • Hepatic TG Lipase (HL) - degrades TG in IDL –> LDL
126
Q

Lipid transport

A

Intestine: makes chylomicrons (pancr enzymes degrade)

  • Chylomicrons –> FFAs or chylomicron remnants (via LPL)
  • Remnants taken up by liver

Liver makes VLDL:

  • VLDL –> IDL (via LPL)
  • IDL –> LDL via HL
127
Q

Lipoprotein fxn

A

Lipoproteins - made of cholesterol, TG, and phospholipids

  • LDL and HDL carry most cholesterol
  • LDL - transports cholesterol from liver to tissues [*LDL = Lousy]
  • HDL - transports cholesterol from periphery to liver [*HDL = Healthy]

Size: chylomicron > VLDL > IDL > LDL > HDL

128
Q

Chylomicron

A

Deliver dietary TGs to peripheral tissue

  • Deliver cholesterol to liver as chylomicron remnants (depleted to triacylglycerols)
  • Secreted by intestinal epithelial cells (villi of duodenum)
129
Q

VLDL

A

Very low-density lipoprotein

  • Made in liver, delivers hepatic TGs to periph tissue
  • Converted to IDL in bloodstream
130
Q

IDL

A

Intermediate-density lipoprotein

  • Formed from VLDL degradation, delivers TG/cholesterol to liver and circulation
  • ApoE and B-100
131
Q

LDL

A

Low-density lipoprotein

  • Formed by hepatic lipase modific of IDL in periph tissues
  • Deliver hepatic cholesterol to tissues
  • Take up by receptor-mediated endocytosis (LDL-R)
  • Deliver fat to macrophages in artery walls
  • ApoB-100
132
Q

HDL

A

High-density lipoprotein

  • Secreted in liver and intestine; alcohol incr synthesis
  • Mediates reverse cholesterol transport from periphery to liver
  • Remove fat from cells = decr atherosclerosis!
  • Also stores ApoC/ApoE (needed to metabolize chylomicrons + VLDL)
133
Q

Familial dyslipidemias

A

I - hyperchylomicronemia
IIa - familial hypercholesterolemia
IV - hypertriglyceridemia

134
Q

Hyperchylomicronemia

A

AR, Type I familial dyslipidemia

  • Incr chylomicrons, TG, cholesterol
  • Lipoprotein lipase (LPL) deficiency or altered ApoC-II
  • Sx: pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas
  • NO incr atherosclerosis risk
135
Q

Familial hypercholesterolemia

A

AD, Type II familial dyslipidemia

  • Incr LDL, cholesterol
  • Absent/defective LDL-R
  • Sx: accelerated atherosclerosis (MI <20 yo), achilles tendon xanthomas, corneal arcus
  • Heterozygotes cholesterol = 300; homozygotes cholesterol = 700
136
Q

Hypertriglyceridemia

A

AD, Type IV familial dyslipidemia

  • Incr VLDL, TG <– hepatic overproduction of VLDL
  • Sx: pancreatitis

Biochemistry (6 decks)

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