Metabolism Flashcards
0
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Mitochondria metabolism
A
Fatty acid oxidation (B-oxid), acetyl-CoA production, TCA cycle, oxidative phosphorylation
1
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Metabolism sites
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Mitochondria
Cytoplasm
Both
2
Q
Cytoplasm metabolism
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Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis
3
Q
Both
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Heme synthesis, Urea cycle, Gluconeogenesis
“HUGs take two (both)”
4
Q
Enzyme terminology
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Enzyme name describes fxn
5
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Kinase
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Uses ATP to add high-energy phosphate to substrate
- Phosphofructokinase
6
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Phosphorylase
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Adds inorganic phosphate onto substrate without ATP (glycogen phosphorylase)
7
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Phosphatase
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Removes phosphate group from substrate
8
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Dehydrogenase
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Catalyses oxidation-reduction rxn
9
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Hydroxylase
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Adds hydroxyl group (-OH) to substrate
10
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Carboxylase
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Transfers CO2 groups with help of biotin
11
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Mutase
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Relocates fxnal group within molecule
12
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Rate limiting step of glycolysis
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Phosphofructokinase (PFK-1)
13
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Rate limiting step of gluconeogenesis
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Fructose-1,6-bisphsphatase
14
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Rate limiting step of TCA cycle
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Isocitrate dehydrogenase
15
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Rate limiting step of Glycogenesis
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Glycogen synthase
16
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Rate limiting step of Glycogenolysis
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Glycogen phosphorylase
17
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Rate limiting step of HMP shunt
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Glucose-6-phosphate dehydrogenase (G6PD)
18
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Rate limiting step of de novo pyrimidine synthesis
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Carbomoyl phosphage synthetase II
19
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Rate limiting step of de novo purine synthesis
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Glutamine-phosphoribosylpyrophospage (PRPP) amidotransferase
20
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Rate limiting step of urea cycle
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Carbomyl phosphate synthetase I
21
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Rate limiting step of Fatty acid synthesis
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Acetyl-CoA carboxylase (ACC)
22
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Rate limiting step of Fatty acid oxidation
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Carnitine acyltransferase I
23
Q
Rate limiting step of Ketogenesis
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HMG-CoA synthase
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Rate limiting step of cholesterol synthesis
HMG-CoA reductase
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ATP production
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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ATP carrier molecule
phophoryl groups
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NADH, NADPH, FADH2 carrier molecule
Electrons
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CoA and lipoamide carrier molecules
Acyl groups
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Biotin carrier molecules
CO2
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Tetrahydrofolates carrier molecules
1-C units
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SAM carrier molecules
CH3 groups
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TPP carrier molecules
Aldehydes
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Universal electron acceptors
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
34
Glucose --> glucose-6-P via hexokinase vs. glucokinase
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
35
Glycolysis regulation
Glucose + 2Pi + 2ADP + 2NAD+ --> 2 pyruvate + 2ATP + 2NADH + 2H+ + 2H2O
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Parts of glycolysis rxn needing ATP
- 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
37
Parts of glycolysis rxn producing ATP
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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Gluconeogenesis
F 1,6BP --> F-6-P (via fructose bisphosphatase 1 = F1,6BPase)
39
Regulation of glycolysis vs. gluconeogenesis via F-2,6BP
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
40
Pyruvate dehydrogenase complex
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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Pyruvate dehydrogenase rxn
Pyruvate + NAD+ + CoA --> acetylCoA + CO2 + NADH
Activated by exercise, increases:
- NAD+/NADH ratio
- ADP
- Ca+2
42
Pyruvate dehydrogenase deficiency
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"
43
Pyruvate metabolism
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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TCA Cycle = Krebs cycle
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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Electron transport chain
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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ATP made w/ ATP synthase
1 NADH --> 2.5 ATP
| 1 FADH --> 1.5 ATP
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Poisons of oxidative phosphorylation
- Electron transport inhibitors
- ATP synthase inhibitors
- Uncoupling agents
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Electron transport inhibitors
Directly inhibit electron transport --> get decreased proton gradient, blocks ATP synthesis
- Rotenone, cyanide, antimycin A, CO
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ATP synthase inhibitors
Directly inhibit mitochondrial ATP synthase --> incr proton gradient
* No ATP made bc electron transport stops
- Oligomycin
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Uncoupling agents
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
51
Gluconeogenesis
- 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)
52
Irreversible enzymes of gluconeogenesis
- 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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Oxidative reaction of HMP shunt
Irreversible:
- G-6-P --> 2NADPH + Ribulose-5P
* Via G6PD; NADPH inhibits G6PD
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HMP shunt
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
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Nonoxidative reaction of HMP shunt
Reversible:
- Ribulose 5P Ribose 5P, G3P, F6P
* Via phosphopentose isomerase or transketolases
56
Respiratory burst (oxidative burst)
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)
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Enzymes of oxidative burst of phagolyosome
- 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
Chronic granulomatous disease and oxidative burst
* *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
Myeloperoxidase deficiency
MPO deficiency
- Can't convert H2O2 to bleach
- Incr candida infections
- NBT normal (bc NADPH intact; MPO not intact)
60
P. aeruginosa and ROS
Pyocyanin of P. aeruginosa makes ROS to kill competitive microbes
61
Lactoferrin
Found in secretory fluids/neutrophils, inhibits microbial growth via iron chelation
62
G6PD deficiency presentation
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
G6PD deficiency pathophys
* 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
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D/o of fructose metabolism
More benign than d/o of galatose metabolism
- Essential fructosuria - benign
- Fructose intolerance
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Essential fructosuria
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
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Fructose intolerance
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)
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D/o of galactose metabolism
- Galactokinase deficiency (infantile cataracts)
- Classic galatosemia (liver, brain and cataracts; more severe)
*Dipstick neg (specific to glucose), reducing sugar in urine
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Classic galactosemia
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
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Galactokinase deficiency
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
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FAB GUT
Fructose is to adolase B, as Galactose is to UridylTransferase
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Sorbitol
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
Lactase deficiency presentation
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
Lactase deficiency pathophys
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
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Amino acids
Only L-form are in proteins
- Essential - need supplementation in diet
- Acidic
- Basic
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Urea cycle
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
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Transporters of ammonia
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)
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Hyperammonemia
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
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N-acetylglutamate deficiency
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
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Ornithine transcarbamylase deficiency
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
Catecholamine synthesis/tyrosine catabolism
Phenylalanine --> Tyrosine --> DOPA (dihydroxyphentlalanine) --> DA --> NE --> Epi --> Metanephrine --> VMA
- DA --> homovanillic acid
- NE --> normetanephrine --> vanillylmandelic acid (VMA)
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Defects in catecholamine synthesis
Defects:
- Phenylalanine to tyrosine = PKU
* Phenylalanine hydroxylase
- DOPA to melanin = albinism
* Tyrosinase
82
PKU presentation
- 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
PKU = phenylketouria pathophys
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
Maternal PKU
Lack of proper diet therapy in pregnancy
| - Infants: microcephaly, intellectual disability, growth retardation, congenital heart defects
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Alkaptonuria
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)
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Cystinuria
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
Homocystinuria
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
Maple syrup urine disease
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)"
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Insulin production
- Pre-proinsulin --> inserts into ER, cleave off "pre" part --> proinsulin (made into C-peptide and insulin)
- Insulin a/B chains combine
90
Homocysteine pathway
Methionine cystathionine --> cysteine
* Methionine (via homocysteine methytransferase, B12, folate)
* Cystathionine (via cystathionine synthase, B6, serine)
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Glycogen regulated by insulin and glucagon/epinephrine
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
Glycogen structure
```
Branches = a(1,6) bonds
Linkages = a(1,4) bonds
```
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Glycogen in skeletal muscle
Glycogenolysis:
- Glycogen --> glucose-1-phosphate --> glucose-6-P
* *Rapidly metabolized during exercise
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Glycogen in hepatocytes
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
Glycogen storage diseases
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
Type I glycogen storage disease
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
Type III glycogen storage disease
AR, Cori disease. Debranching enzyme (a1,6-glucosidase)
| - Milder version of Type I, nl blood lactate
98
Type II glycogen storage disease
AR, Pompe disease. Lysosomal a1,4 glucosidase (acid a glucosidase = acid maltase)
- Cardiomyopathy, hepatomegaly, early death; "Pompe trashes Pump"
99
Lysosomal storage diseases
Deficiency of lysosomal enzymes
| - Get accumulation of abn metabolic products
100
Type IV glycogen storage disease
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
Fabry disease
X-linked recessive, deficient a-galactosidase A
- Peripheral neuropathy of hands/feet, angiokeratomas, CV/renal disease
* Accumulate ceramide trihexoside
102
Gaucher disease
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
Niemann-Pick disease
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
Tay-Sachs disease
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
Krabbe disease
AR, Galactocerebrosidease defic
- Peripheral neuropathy, dx delay, optic atrophy, globoid cells
* Accumulate galactocerebroside
106
Metachromatic leukodystrophy
AR, arylsulfatase A defic
- Central/periph demyelination w/ ataxia, dementia
* Accumulate Cerebroside sulfate
107
Hurler syndrome
AR, a-L-iduronidase defic
- Dx delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
* Accumulate heparan sulfate, dermatan sulfate
108
Hunter syndrome
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
Fatty Acid degradation
* 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
Fatty Acid synthesis
* Requires citrate shuttle for citrate to get out of mitochondrial matrix
- Citrate --> shuttle --> Acetyl-CoA --> FA synth
111
Carnitine deficiency
Can't transport LCFAs into mitochondria, get toxic accumulation
- Sx: weakness, hypotonia, hypoketotic hypoglycemia
112
Acyl-CoA dehydrogenase
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
Ketone bodies
Liver: FAs and AAs broken down into acetoacetate and B-hydroxybutyrate (ketones) for muscle use
- Acetyl-CoA branches to TCA, FAs or ketones
114
Causes of increased ketone bodies
- 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
Testing for ketones
- Breath smells like acetone (fruity)
| - Urine test for ketones doesnt pick up B-hydroxybutyrate
116
Energy (kcal) per type
- Protein/carb = 4kcal
- Fat = 9kcal
- Alcohol = 7kcal
117
Metabolic fuels use in exercise
- Stored ATP - 2 s
- Creatinine phosphate - 10s
- Anaerobic metabolism - 1 min
- Aerobic metabolism - >1 min
118
Regulation in fasting/starvation states
*Main goal to supple glucose to brain and RBCs
119
Fed state (after meal)
Glycolysis and aerobic respiration
| *Insulin stimulates storage of lipids, proteins, glycogen
120
Fasting state (btwn meals)
Hepatic glycogenolysis (major)
Hepatic glucogenolysis, adipose release of FFA (minor)
*Glucagon + adrenaline stimulate use of fuel reserves
121
Starvation day 1-3
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
Starvation after day 3
Adipose sotres - ketone bodies main source of energy for brain
- After depleted, accelerates protein degradation - organ failure/death
- More stores = longer survival time
123
Cholesterol synthesis
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
Statins and cholesterol synthesis
HMG-CoA reductase = rate-limiting enzyme
| - Statins competitive/reversibly inhibit HMG-CoA reductase --> inhibits cholesterol synthesis
125
Lipid transport enzymes
- 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
Lipid transport
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
Lipoprotein fxn
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
Chylomicron
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
VLDL
Very low-density lipoprotein
- Made in liver, delivers hepatic TGs to periph tissue
- Converted to IDL in bloodstream
130
IDL
Intermediate-density lipoprotein
- Formed from VLDL degradation, delivers TG/cholesterol to liver and circulation
* ApoE and B-100
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LDL
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
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HDL
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)
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Familial dyslipidemias
I - hyperchylomicronemia
IIa - familial hypercholesterolemia
IV - hypertriglyceridemia
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Hyperchylomicronemia
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
Familial hypercholesterolemia
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
Hypertriglyceridemia
AD, Type IV familial dyslipidemia
- Incr VLDL, TG <-- hepatic overproduction of VLDL
- Sx: pancreatitis
