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Biochem BLOCK 2 > Deevska-Block 2 > Flashcards

Deevska-Block 2 Flashcards

1
Q

Where is pyruvate oxidiized to acetyl CoA?

A

Mitochondrial matrix

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2
Q

What molecules are produced in the TCA cycle?

A

-3 NADH
-1 FADH
1 GTP

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3
Q

How is glycolysis and TCA linked?

A

Pyruvate is the end product of glycolysis which goes to the TCA cycle. PDH converts it to acetyl Coa, which combines with oxaloacetate to form citrate (with enzyme citrate synthase) to go into the actual cycle

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4
Q

Explain the function and structure of the PDH complex

A
  • 3 separate enzymes (E1, E2, E3)
  • 5 different cofactors
    • TPP
    • lipoamide
    • CoA
    • FAD
    • NAD
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5
Q

What are the cofactors of PDH?

A
  • TPP
  • lipoamide
  • CoA
  • FAD
  • NAD
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6
Q

What activates PDH?

A
  • dephosphoryaltion
  • pyruvate
  • NAD+
  • ADP
  • Ca2+
  • CoA
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7
Q

What deactivates PDH>?

A
  • acetyl CoA
  • NADH
  • ATP
  • phosphorylation
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8
Q

PDH and deficiency of niacin or thiamine

A

Can cause serious CNS problems

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9
Q

Arsenic poisoning

A

Males lipoic acid unavailable as coenzyme for PDH

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10
Q

Sequence of reactions in TCA

A
  1. Synthesis of citrate from acetyl CoA and oxaloacetate (citrate synthase)
  2. Isomerization of citrate to isocitrate (aconitase)
  3. Oxidative decarboxylation of isocitrate to a-ketoglutarate (isocitrate dehydrogenase)
  4. Oxidative decarboxylation of a-ketoglutarate to succinyl CoA (a-ketoglutarate dehydrogenase complex)
  5. Cleavage of succinyl CoA to Succinate (succinyl CoA synthetase or succinate thiokinase)
  6. Oxidation of succinate to fumarate (succinate dehydrogeanse)
  7. Hydration of fumarate to malate (fumarase)
  8. 1 oxidation of malate to regenerate oxaloacetate and produce NADH + H+ (malate dehydrogenase)
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11
Q

Identify the 4 oxidative enzymes in the TCA cycle, their products, and regulation

A

PDH

  • product is acetyl CoA
  • activated by: pyruvate, NAD+, ADP, Ca2+, CoA, dephosphorylation
  • deactivated by acetyl CoA, NADH, ATP, phosphorylation

Isocitrate dehydrogenase

  • product is a-ketoglutarate
  • inhibited by: ATP, NADH
  • activated by: ADP, Ca2+

A-ketoglutarate dehydrogenase

  • product succinyl CoA
  • inhibited by: products
  • activated by Ca2+

Succinate dehydrogenase
-product: fumarate

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12
Q

What are the 4 oxidative enzymes of the TCA?

A
  • PDH
  • isocitrate dehydrogenase
  • a-ketoglutarate dehydrogenase
  • succinate dehydrogenase
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13
Q

Identify the 2 intermediates required in the first step of the TCA cycle and their metabolic sources.

A
  • OAA and pyruvate
  • pyruvate comes from glycolysis as the end product and is changed into acetyl CoA via PDH
  • OAA is just cycled through TCA over and over again
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14
Q

Identify 4 important products synthesized from the TCA cycle and summarize the energy yield for 1 glucose molecule

A
  • 2 CO2
  • 3 NADH
  • 2 FADH
  • 1 GTP
  • 36-38 ATP overall
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15
Q

Identify the enzymes from the TCA cycle affected by vitamin deficiency and arsenic poisoning and explain the underlying reason for that.

A

Enzymes: PDH and A-ketoglutarate

  • arsenic poisoning forms a stable theology bond with lipoic acid (coenyme for both enzymes) making it unavailable to be used as a coenzyme
  • affects the brain causing neurological disturbance and death
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16
Q

Why don’t we get glucose from TCA?

A

Because PDH is irreversible, we don’t have enzymes to catalyze the reverse reaction

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17
Q

Outline the structure of the mitochondria and the mitochondrial electron transport system showing all major electron carriers.

A
  • electron carriers: NAD+ and FAD
  • outer membrane: permeable to most ions and small molecules
  • innermembrane: impermeable to most small ions and large molecules
  • Matrix: TCA cycle enzymes, FA oxidation enzymes, mitochondrial ribosomes
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18
Q

Electron transport assembly

A

Complex 1-NADH dehydrogenase

  • FMN
  • iron sulfer center

Complex II - succinate dehydrogenase

  • only one embedded in the inner mitochondrial membrane
  • FAD contains iron sulphur center

CoQ

  • ONLY nonprotein carrier
  • quinine derivative

Complex III-cyt b and c1
-heme group which reversible converted from ferric to ferrous

Complex IV-cyt a and a3

  • heme group which reversible converted from ferric to ferrous
  • Cu
  • heme directly reacts with O2

Cyt c
-freely moving in the intermembrane space

Complex V-ATP synthase
-multisubunit

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19
Q

Describe how the TCA cycle is regulated by substrate supply, allosteric effectors, covalent modification, and protein synthesis

A

PDH covalent modifications:
-phosphorylation deactivates
-dephosphorylation activates
-PDH kinase and phosphatase can be allosterically activated or inhibited by substrate activation and product inhibition
Other regulations:
-activation: pyruvate, NAD+, ADP, Ca2+, CoA
-deactivation: acetyl CoA, NADH, ATP

Isocitrate dehydrogenase allosteric regulation

  • inhibitors: ATP and NADH
  • Activators: ADP and Ca2+

A-ketoglutarate dehydrogenase regulation

  • inhibitors: its products
  • activators: Ca2+
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20
Q

Explain the role of uncoupling proteins in thermogensis

A
  • allow H+ to flow back into the matrix without passing though complex V, and not forming ATP
  • the free energy is released as heat (nonshivering thermogenesis)
  • UCP1 (thermogenin) found in brown fat
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21
Q

Give examples of synthetic uncouplers (such as salicylic acid) and their effect on the ETC

A
  • 2,4-dinitrophenol: used as a weight loss drug in the 30s. However its use was banned because it was relatively easy to overdose, which can cause a fatal hyperthermia, although its use still persists (illegally)
  • compounds containing salicylic acid will also cause uncoupling, including aspirin. Overdoses of aspirin will cause a high fever and profuse sweating, and can be potentially fatal
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22
Q

Describe the effects of inhibitors such as rotenone, antimycin A, carbon monoxide, cyanide and oligomycin on oxygen uptake by mitochondria and ETC function

A
  • Amytal: complex I-barbiturate. Importance of proper drug dosage
  • Rotenone: complex I-insecticide, piscicide, and pesticide
  • antimycin A: complex III-pesticide
  • CN-complex IV-irreversibly binds to the Fe3+ in the heme group of cyt c-oxidase
  • CO-complex IV-binds irreversibly- tight binding to hemoglobin
  • NaN3-binds similarly to CN to the Fe3+ of iron in cyt
  • oligomycin-binds to the F0 domain closing the proton channel leading back into the matrix and shutting down ATP synthesis
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23
Q

Describe the role of mitochondria in apoptosis.

A
  • initiated through mitochondria intrinsic pathways resulting in the formation of pores in the outer mitochondrial membrane
  • pores allow cyt C to be released in the cytosol
  • capsases cause cleavage of key proteins that result in the morphological and biochemical changes characteristic of apoptosis.
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24
Q

What disease can result from mutations in the mtDNA or nuclear DNA?

A
  • LHON
  • mycolonic epilepsy with ragged red fibers (MERRF)
  • mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes (MELAS)
  • Leigh syndrome
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25
Q

LHON

A

-optic neuropathy and atrophy

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26
Q

NARP

A
  • Retinal dystrophy

- cone or cone-rod dystrophy

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27
Q

MILS

A
  • RPE dystrophy

- optic atrophy

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28
Q

MELAS

A
  • maculopathy
  • cone-rod dystrophy
  • hemianopsia
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29
Q

MIDD

A
  • pattern maculopathy

- pigmentary retinopathy

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30
Q

MERRF

A
  • optic atrophy

- mild pigmentary retinopathy

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31
Q

KSS

A
  • pigmentary retinopathy

- strabismus ptosis

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32
Q

CPEO

A
  • Ptosis
  • Ophthlmoplegia
  • strabismus
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33
Q

Outline the pathway for GNG, including purpose for the pathway, tissues where it takes place, and sub cellular localization

A

GNG is the metabolic pathway that results in the generation of glucose from non carbohydrate precursors

  • Purpose: the maintain blood glucose levels and avoid hypoglycemia under conditions of fasting (>10-18 hours)
  • tissues: predominant in the liver, in the kidney cortex at a lesser extent only during prolonged fasting contribute up to 40% of the total glucose production
  • subcellular localization:
    • mitochondrial matrix-step 1
    • cytosol-all reversible steps of glycolysis
    • ER-last step (dephosphorylation) to produce glucose
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34
Q

Identify all possible substrates for GNG

A
  1. Glycerol
    -hydrolysis of TAGs in adipocytes, delivered by the
    blood to liver
    -in the liver: glycerol–glycerol phosphate—DHAP
  2. Amino Acids
    -derived from tissue protein hydrolysis (very late in starvation
    mode).
    -Ala is the major AA, but most can be used
    -most AA converted in the TCA can yield OAA
  3. Lactate
    -converted back into pyruvate in liver by lactate dehydrogenase
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35
Q

Can acetyl CoA serve as substrate for GNG?

A

NO

  • cannot be converted into pyruvate in humans
  • PDH is irreversible and no enzyme for the reverse reaction
  • FA CANNOT serve as substrate for GNG
  • FA oxidation provides liver with the energy to perform GNG
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36
Q

Cori Cycle

A

Glucose converted into lactate under anaerobic glycolysis, excreted to plasma and sent to the liver to be converted back to glucose and released into circulation forms this

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37
Q

Reversible steps of GNG

A
  • 7 steps
  • glycolytic steps
  • highly dependent on concentration of substrates and products
  1. Carboxylation of pyruvate to OAA (pyruvate carboxylase)
    -allosterically activated by acetyl CoA
    -OAA cannot be exported (lack of transporters)
    -converted to malate and then converted back to OAA (malate
    dehydrogenase, PEP carboxykinase)
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38
Q

Steps unique to GNG

A

decarboxylation of cytosolic OAA

  • driven by GTP hydrolysis
  • makes GNG energetically possible
  • PEPCK

Dephosphorylation of fructose 1,6-bis-P

  • bypasses PFK-1 reaction
  • important for site regulation
  • fructose 1,6-bisphosphatase

Dephosphorylation of glucose 6-P

  • bypasses hexo/gluco reaction
  • energetically favorable step to produce glucose
  • glucose 6-phosphatase
  • deficiency leads to Von Gierk
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39
Q

What is irreversible in GNG?

A
  • Decarboxylation of cytosolic OAA (PEPCK)
  • Dephosphorylation of fructose 1,6-bis-P (fructose 1,6-bisphosphatase)
  • dephosphorylation of glucose 6-P (glucose 6-phosphatase)
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40
Q

Compare and contrast common (shared) allosteric regulators of enzymes from glycolysis and GNG and understand the biological role of this regulation

A

Regulation by Glucagon

  • inhibits PFK-2, lowers fructose 2,6-BP, inhibiting glycolysis and activating GNG
  • inhibits pyruvate kinase, therefore PEP is used for GNG as opposed to glycolysis
  • stimulates transcription of PEPCK, insulin inhibits

Regulation by fructose 2,6-bisphosphate (synthesized by PFK-2)

  • inactivated fructose 1,6-bisphosphate and stops GNG
  • the common regulator allows tight regulation assuring the pathways of glycolysis and gluconeogensis are mutually exclusive

Allosteric activation by acetyl CoA

  • buildup of acetyl CoA, signals the diversion of OAA for gluconeogensis
  • activates pyruvate carboxylase
  • inhibits PDH, assuring pyruvate is diverted to the production of glucose and away from the TCA cycle

Allosteric inhibition by AMP

  • fructose 1,6 bisphosphate is inhibited by AMP
  • PFK-1 is activated by AMP
  • as with regulation of the two enzymes by fructose 2,6-BP, the reciprocal regulation of each of these enzymes by the same allosteric effector assures the two pathways are mutually exclusive
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41
Q

Summarize the pathway from energetic point of view

A
  • an energy-requiring pathways (endergonic)
  • anabolic pathway
  • for 1 glucose
    • 4 ATP and 2 GTP used
    • 2 NADH are used
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42
Q

Explain all possible ways to regulate GNG

A

-pyruvate carboxylase allosterically activated by acetyl CoA
-fructose 1,6-bisphosphatase
Inhibited by AMO
Allosterically inhibited by fructose 2,6-bis-P
Activated by night ATP, low AMP
-regulation by glucagon
-regulation by substrate availability
-allosteric activation by acetyl CoA
-allosteric inhibition by AMP

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43
Q

Identify the enzymatic step in GNG that will be effected when biotin is not available and explain why

A

Carboxylation of pyruvate to OAA using enzyme pyruvate carboxylase
-pyruvate carboxylase requires biotin as a coenzyme

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44
Q

Outline the metabolic pathways for synthesis and degradation of glycogen including names of enzymes and intermediates. Compare and Contrast liver and muscle cells

A
  1. Synthesis of UDP glucose (hexo/glucokinase, phosphoglucomutase, UDP glucose phosphorylase)
  2. Synthesis of a primer to initiate glycogen synthesis (glycogen synthase and protein glycogenin)
  3. Elongation of glycogen chains (glycogen synthase) rate limiting enzyme
  4. Formation of branches (branching enzyme)
  5. Shortening of chains (glycogen phosphorylase)
  6. Removal of branches (debranching enzyme)
  7. Conversion of glucose 1-P to glucose 6-P (phosphoglucomutase)
  8. Dephosphorylation of glucose6-P to glucose (glucose 6-phosphatase)
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45
Q

Von Gierke

A

Deficient enzyme: glucose 6-phosphatase
Clinical features: severe fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperurecemia, short stature
Glycogen structure: normal

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46
Q

Pompe

A

Deficient enzyme: lysosomal a-glcosidase
Clinical features: cardiomegaly, muscle weakness, death by 2 years
Glycogen structure: glycogen like material in inclusions

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47
Q

Cori

A

Deficient enzyme: debranching enzyme
Clinical features: mild hypoglycemia, liver enlargment
Glycogen structure: short outer branches, single glucose residue at outer branch

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48
Q

McArdle

A

Deficient enzyme: muscle glycogen phosphorylase
Clinical features: muscle cramps and weakness on exercise, myoglobinuria
Glycogen stucture: normal

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49
Q

Anderson

A

Deficient enzyme: branching enzyme
Clinical features: infantile hypotonia, cirrhosis, death by 2 years
Glycogen structure: very few branches, especially towards periphery

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50
Q

Hers

A

Deficient enzyme: hepatic glycogen phosphorylase
Clinical features: Mild fasting hypoglycemia, hepatomegaly, cirrhosis
Glycogen structure: normal

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51
Q

Outline the sources of fructose and galactose and explain their biological roles

A

Fructose

  • significant source of calories in western diet
  • sucrose, high fructose corn syrup, honey, fruits
  • entry not insulin dependent
  • mediated by glut 5 transporter
  • does not promote insulin secretion
  • bypasses PFK1 step, metabolized more rapidly than glucose

Galactose

  • isomer of glucose
  • lactose from milk and milk products
  • some from lysosomal degradation of complex carbs
  • not insulin dependent
  • 2-steps to UDP galactose
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52
Q

Explain why these two simple sugar molecules are metabolized faster compared to glucose?

A

Because they bypass the PFK-1 step and do not require insulin

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53
Q

Outline the steps of fructose metabolism

A
  1. phosphorylation of fructose
    - enzyme in liver: fructokinase
    - enzyme in other tissue: hexokinase
  2. Cleavage of fructose 1-P
    - enzyme: Aldolase B
    - products: DHAP and glyceraldehyde
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54
Q

Outline the steps of galactose

A
  1. phosphorylation of galactose
    - enzyme: galactokinase
  2. Formation of UDP galactose
    - enzyme: GALT
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55
Q

Essential fructosuria

A

Lacking: fructokinase
Results: fructose accumulates in the urine

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56
Q

Describe the conversion of glucose to fructose via sorbitol and explain how accumulation of sorbitol leads to pathology in certain tissue types

A
  • excess glucose gets converted into sorbitol, sorbitol accumulation results in osmotic uptake of water, which can account for some of the symptoms seen in dim patients including
  • cataracts
  • retinopathy
  • nephropathy
  • peripheral neuropathy
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57
Q

Hereditary fructose intolerance (fructose poisoning)

A

Lacking: aldolase B
Results: severe hypoglycemia, vomiting, jaundice, hemorrhage, hepatomegaly, renal dysfunction, hyperurcemia, lactacidemia
-hepatic failure and death

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58
Q

Galactokinase deficiency

A

Lacking: galactokinase
Results: cataracts

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59
Q

Aldose reductase elevation

A

Too much: aldose reductase

Results: cataracts

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60
Q

Classic galactosemia

A

Lacking: GALT
Results: liver damage, severe mental retardation, and cataracts

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61
Q

Describe where, when, and how lactose can be synthesized in humans

A
  • milk sugar produced by lactating mammary glands
  • synthesized in the golgi
  • enzyme: lactose synthase
    • a-lactalbumin synthesis is stimulated by the peptide hormone prolactin
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62
Q

What are all the names for the penthouse phosphate pathways

A
  • pentose phosphate pathway

- hexosemonophosphate (HMP) shunt

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63
Q

Describe the purpose of PPP and its role as a source of NADPH and in the synthesis of ribose for nucleotide synthesis

A
  • generation of NADPH and generation of the 5-carbon sugar ribose, to be used in the synthesis of nucleotides
  • The pathway can produce both ribose and NADPH, or it can produce only NADPH or only ribose, depending on the needs of the cell. No ATP is produced or used during this process
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64
Q

Describe the stages of PPP including all enzymes and their regulators (or coenzymes) outlined in the lecture notes and be able to compare and contrast the types of biochemical reactions in each stage (phase)

A 
1. Dehydrogenation of glucose 6-P
   Enzyme: G6PD, NADP+ is coenzyme
   Upregulated by insulin
   Flux increases in absorptive state
   RATE LIMITING STEP
2. Hydrolysis to 6-phosphogluconate
   Enzyme: 6-phosphogluconolactone hydrolase 
   Produces one NADPH
   Irreversible
3.oxidative decarboxylation of 6-phosphogluconate
   Enzyme: 6-phosphogluconate dehydrogenase
   Produces 1 NADPH
   Irreversible
4-8. Interconversions of sugar molecules
   Reversible steps
   Permit synthesis of ribose 5-P used for nucleotide production
   Enzyme: transketolase, requires TPP
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65
Q

Explain the differences between NADH and NADPH function and structure

A
  • NADH has and OH group
  • NADPH has -OPO3-2 where the PH group would be
  • both electron carriers
  • NADPH-electron carrier for reductive biosynthesis of FA, cholesterol, and steroids
  • provides reducing equivalents for cyt P450 monooxygenase system
  • play a role in phagocytosis
  • substrate for the synthesis of NO
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66
Q

Describe the structure and function of GSH and GSSG

A
  • NADPH role in neutralization of ROS
  • tripeptide GSH
  • major antioxidant system is GSSG/GSH
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67
Q

NADPH roles in cyt P450 system

A

-monooxygenase

has a mitochondrial system for synthesis of steroids

  • inner mitochondria membrane
  • steroidogenic tissue uses NADPH for synthesis of steroid hormones
  • in liver to synthesize biles acids and vitamin D3
  • in kidney converts D3 to active form

has a microsomal like system for detox of drugs

  • smooth ER in liver cells
  • detox of drugs
  • adding oxygen to inactivate
68
Q

NADPH role in phagocytosis

A
  • neutrophils and macrophages
  • generation of O free radicals aid in killing microorganism
  • MPO system
69
Q

Describe the role of MPO system in phagocytosis

A

-combination of NADPH oxidase and myeloperoxidase are used to generate the oxygen free radicals to aid in the destruction of microorganism

70
Q

NADPH oxidase deficiency

A
  • causes chronic granulomatous disease (CGS)
  • persistent severe high infections due to the inability to kill bacteria forming granulomas
  • the granuloma is formed as a defense where the body attempts to wall off the collective cells from the rest of the body
71
Q

Outline the biological functions of NO

A
  • smooth muscle relaxant (the basis for nitroglycerin action which is converted to NO to relax vascular smooth muscle)
  • used by macrophages to generate free radicals to assist in killing micro organisms
  • inhibits platelet aggregation
  • functions as neurotransmitter in brain
72
Q

Explain the consequences of genetic defects of G6P D deficiency and know the specific features of it in RBCs

A

-inability to detox drugs
-one of the most common single gene disorders
-some protection against malaria
-usually only symptomatic when experiencing an oxidative stress
Infections
Drugs that produce an oxidative stress
Fava beans

  • episodic hemolytic anemia in adults because the NADPH in RBCs can only come from this pathway whereas other tissues have other means of getting it
  • CANNOT synthesize more G6PD since they lack nucleus
  • affect stability, enzyme lost and not replaced
  • produces Heinz bodies which are precipitates of oxidized hemoglobin
73
Q

Difference between saturated and mono-, polyunsaturated fatty acid

A
  • saturated: NO DOUBLE BONDS

- unsaturated: carbons have 1 or more double bonds

74
Q

Tm

A
  • double bonds reduce it

- increasing chain length increases it

75
Q

How to name structure omega 3 or omega 6

A

20:4(5,8,11,14). 20-14= 6…omega 6

76
Q

What are the two essential FA? Why?

A
  • linoleic acid, because it is a precursor for other shorter omega 6 FA
  • a-linolenic acid because it is a precursor for omega 3 FA: important for growth and development
77
Q

What FA can become essential and why?

A

Arachidonic acid

  • substrate for prostaglandin synthesis
  • becomes essential if a-linolenic acid is absent
78
Q

What are arachidonic acid and a-linolenic acid precursor for?

A

Omega 3 FA

79
Q

What are the categories of FA length?

A

4 of them

-short, medium, long, very long

80
Q

What kind of FA are there?

A

Free

Esterified

81
Q

General type of lipids that are digested

A

CE
PL
TAG

82
Q

Enzymes that function to digest dietary lipids

A

Gastric lipase

  • acid lipase, secreted from the gastric mucosa
  • optimal at lower pH in stomach
  • target TAG containing short and medium chain FA in stomach

Lingual Lipase
-acid lipase, secreted from glands at back of the tongue, same as gastric lipase on everything else

Pancreatic lipase

  • TAG digestion, in pancreas, cleaves FA producing 2 free FA and a 2-monoacylglycerol
  • high catalytic efficiency

Coplipase

  • secreted from pancreas and binds pancreatic lipase
  • promoted pancreatic lipase activity when inhibitory bile salts are present

Cholesterol esterase

  • pancreatic enzyme responsible for cholesteryl ester digestion
  • digests esterified cholesterol

Phospholipids A2
-phospholipid digestion, pancreas, removes FA to produce lysophospholpid

Lysophospholipase
-phospholipid digestion, pancreas, glycerylphosphoryl group

83
Q

Importance for emulsification of dietary lipids, where it happens, aspects important for making emulsification possible

A

Mechanical agitation
-dietary material via peristalsis increases the lipid droplet surface area

Bile salts secretion

  • made in liver
  • stored in gallbladder
  • secreted to small intestine
  • detergent properties prevents from coalescing
84
Q

Which of the phosphoryl bases are likely to be taken up?

A

Cholic acid

  • bile salt production
  • lung surfactant production
85
Q

What are the two hormones made and released by gut endocrine cells

A

CCK

  • promotes pancreatic enzyme secretion
  • causes gall bladder to release bile, bile salts, phospholipids, free cholesterol
  • reducing release rate of gastric contents

Secretin

  • low pH of chyme entering the intestines
  • promotes the release of bicarbonate rich solution from the pancreas.
86
Q

Components found in bile

A

Glycine and cholic acid

87
Q

Components found in micelles from diet and from bile. Including the fat soluble vitamins DEAK

A 
Disk shaped clusters of AMP hips this lipids
Formed from
-bile salts
-digested lipids
-fat soluble vitamins (DEAK)
88
Q

Promotion of micelle formation

A

Digested lipids and the manner in which it is done promotes it.
Many of the molecules generated during digestion are ampipathic in nature

89
Q

What does not require micelle transportation

A

Short and medium chain FA

90
Q

What is taken up by enterocytes

A

Digested lipid components and components of the bile which end up in the micelles.

91
Q

Long chain FA entering the enterocytes

A

Charged to CoA by thiokinase and then re esterified to form TAG, CE, and some phospholipids

92
Q

Components of chylomicrons

A

Apolipoprotein B-48

Distributed to lymph then circulated in the blood

93
Q

What happens to chylomicron remnant?

A

Taken up by liver, along with the remaining components associated with the remnant

94
Q

Lipid malabsorption cause, effect, treatment

A

Cause: decreased bile excretion, pancreatic insufficiency, defective enterocytes, shortened bowel
Effects: reduce dietary calories, fat soluble vitamin deficiency, could result in essential FA deficicney
-treatment: increase calorie from non-fat sources, fat soluble vitamin supplements, enzyme replacement therapy

95
Q

Know where FA synthesis occurs, what is the cytosolic carbon source, what is the energy source, and what functions as a reducing agent

A

FA synthesis occurs in the cytosol

  • cytosolic acetyl CoA is the carbon source
  • energy source is ATP and NADPH
96
Q

Where are the carbons for FA synthesis originally?

A

In the mitochondria

-in the form of Acetyl CoA but CoA cannot traverse the inner mitochondrial membrane to the cytosol

97
Q

How do the acetate carbons get across the inner mitochondrial membrane?

A

acetyl CoA and OAA come together and form citrate via citrate synthase and can now cross the membrane.

98
Q

What does ACC do? How is it regulated short term and long term?

A
  • carboxylase cytosolic acetyl CoA to malonyl CoA
  • uses CO2 and energy from ATP hydrolysis to carboxylase the acetyl group of acetyl CoA
  • provides the energy for C-to-C condensations to elongate the growing FA chain
  • carboxylation of the acetyl CoA is the rate limiting and regulating step for FA synthesis

Short term regulation

  • inactive ACC diners are allosterically activated to its polymerized form by citrate
  • AMPK reversibly phosphorylates and inhibited ACC when fasting
  • indirectly inhibited by epinephrine and glucagon

Long term regulation

  • prolonged high calorie, high carb diets increase ACC synthesis which increase FA synthesis
  • a low calorie or high fat diet reduces FA synthesis by decreasing ACC synthesis
99
Q

FAS

A
  • multifunctional dimeric enyme that has two important sites
  • ACP
  • cysteine residue holding site
100
Q

4 steps of FAS

A

First, a Tate from acetyl CoA is transferred to ACP site on FAS
A. Acetate transferred to cysteine residue holding site
B. Malonate from malonyl CoA transferred to ACP site on FAS
C. Energy from decarboxylation of the malonyl ACP drives a condensation reaction between the ACLU group at the holding site cysteine and the remains acetyl ACP
D. The 4-carbon is transferred to the cysteine holding site.

Repeat these steps 6 more times and with each cycle add 2 carbons

Inbetween each cycle, NADPH function as reducing agents, which majorly comes from HMP pathway

101
Q

Where does FA elongation and desaturation occur?

A

Smooth ER

102
Q

Where are VLCFAs made?

A

Brain

103
Q

Storage of FA as TAG

A

Carbon 1: saturated FA
Carbon 2: unsaturated FA
Carbon 3: either sat or unsat FA

104
Q

What are the two processes/pathways to produce glycerol phosphate? Which pathway is possible in adipose and liver tissue and which pathway is Preston only in the liver?

A

A. In liver and adipose tissue: produced from glucose via the glycolytic pathway
B. In liver only: glycerol kinase converts free glycerol to glycerol phosphate

105
Q

How is TAG molecule generated?

A

Thiokinase transfers 2 fatty acyls from acyl-CoAs to a glycerol phosphate, the phosphate is removed by a phosphatase and replaced with an additional fatty acyl from acyl-CoA

106
Q

Know the two enzymes in the adipose that release FA from TAG

A

Adipose lipase: constitutive FA release
HSL: major role in regulated TAG lipolysis and release of FA from adipose
-phosphorylated and activated by cAMP dependent protein kinases (fasting) (binds to perilipin)
-epinephrine phosphorlyates and activates it
-insulin promote dephosphorylation

107
Q

Fate of glycerol

A
  • adipocytes lack glycerol kinase and cannot metabolize glycerol released in TAG degradation
  • glycerol is:
    • phosphorylated in the liver to be used in TAG synthesis or
    • reversibly converted to DHAP by glycerol phosphate dehydrogenase
    • DHAP can participate in glycolysis or gluconeogensis
108
Q

Which two tissues cannot use FAs for energy?

A

Brain and erythrocytes

109
Q

Where doe B-oxidation occur and what are the products?

A
  • mitochondria

- acetyl CoA, NADH, FADH2

110
Q

How does the carnitine shuttle work

A
  1. Acyl groups are transferred from CoA to carnitine by CAT1, an outer mitochondrial membtane enzyme
  2. Acyl carnitine is transported into the mitochondrial matrix in exchange for free carnitine by carnitine-acyl carnitine tranlocase
  3. CATII on the matrix side of the inner mitochondrial membrane catalyze acyl group transfer from carnitine to CoA
111
Q

Why is carnitine shuttle important for VLCFA?

A

LCFA cannot directly cross the inner membrane of the mitochondria due to the presence of the CoA

112
Q

How is CATI regulated and why is

A
  • CAT I is inhibited by malonyl CoA in well fed
    • preventing LCFA transfer from CoA to carnitine

This inhibition prevents

  • mitochondrial import and B-oxidation of newly synthesized LCFAs
  • B-oxidation of LCFAs to generate energy while in a well fed state
113
Q

How is most carnitine obtained, where is it made de novo, where is most of it located/utilized, what could cause a deficiency of carnitine?

A

Source:
-diet (meat) or synthesized

Where is it synthesized?
- by an enzymatic pathway in the liver and kidney using AA lysine and methionine

Where is it located/utilized?
Skeletal muscle

Deficiency cause

  • decreased synthesis due to liver disease
  • dietary malnutrition
  • hemodialysis
  • conditions in which carnitine requirements increase
  • CAT I GENETIC DEFECT (decrease liver use)
  • CAT II GENETIC DEFECT (heart and skeletal muscle)
114
Q

Why do short and medium chains not require carnitine shuttle?

A

FA

115
Q

When a FA is B-oxidized in a muscle cell, considering all molecules being generated, how is that energy being extracted: consider the ETC (NADPH, FADH2), and TCA cycle ( acetyl CoA)

A
  1. Oxidation producing FADH2 which can be used for ETC
  2. Simple hydration reaction
  3. Another oxidation that produces NADH which can also go to ETC
  4. Release acetyl CoA which can be used for GNG if it’s carboxylated by pyruvate carboxylase
116
Q

B-oxidation of FAs with odd number of carbons

A

-require biotin and the coenzyme form of vitamin B12

117
Q

B-oxidation of unsaturated FAs

A

-requires additional enzymes and produce less energy than saturated FAs

118
Q

VLCFA B-oxidation

A

Require additional step in peroxisome that generate no ATP

119
Q

Branched chain FA require what?

A

A-oxidation in the peroxisome by PhyH and with its deficiency, phytanic acid accumulates in blood and tissues resulting in neurologic conditions (refsum disease) requires dietary restriction of phytanic acid to halt progression of the disease

120
Q

MCAD deficiency

A
  • results in the inability to oxidize 6-10 carbon FA, accumulation of them, measurable in the urine, resulting in severe hypoglycemia due to tissue reliance on glucose for energy. Treatment is to avoid fasting
  • linked to SIDS
121
Q

What are the 3 ketone bodies?

A
  • acetoacetate
  • 3-hydroxybutarate
  • acetone

Acetone is a volatile, dead-end ketone body that is exhaled

122
Q

Conversion of ketone bodies back into acetyl CoA

A

Heart, skeletal, and renal cortex can do this and use them in the TCA cycle for energy, but liver cannot

123
Q

FA oxidation disorders

A

Hypoketosis, hypoglycemia

124
Q

Rate limiting and irreversible step of ketogensisi

A

Conducted by HMG CoA synthase

Almost exclusively in the liver

125
Q

Imbalance use and production of ketone bodies

A

Can result in ketonemia (increase blood level ketone bodies), and ketouria (urine level ketone bodies to increase

126
Q

Diabetic ketoacidosis

A
  • causes fruity smelling breath from acetone
  • ketonemia causes acidemia because the carboxyl group on keton bodies has a pKa of about 4, lowers pH
  • increased ketone bodies and glucose cause increased secretion of water and dehydration
  • ketoacidosis: decreased blood volume increases H+ cxn causing severe acidosis
  • can be caused by fasting
127
Q

Explain how the structure determines the functions of glycerophospholipids and sphingomyelin

A

All glycerol and sphingomyelin are amphipathic. Able to arrange themselevs in the plasma membrane spontaneously when reacted with water

128
Q

List the predominant phospholipids in tears and be able to identify all phospholipids that are associated with the eye

A

Phospholipids associated with the eye:

  • PC
  • PS
  • SM
  • PE
  • PG
  • dihydrosphingomyelin
  • ethanolamineplasmalogen
  • lysophosphatidylcholine
  • phosphatidylinisotol

Predominant ones in tears
-PE, PC,SM

129
Q

Describe the general structure and most important functions of PA

A
  • precursor for the synthesis of all other glycerophospholipids and TAG
  • signaling molecule
  • influence membrane curvature and vesicle formation
  • simplest of all phospholipids
130
Q

Describe the general structure and most important functions of PC

A
  • also called lecithin
  • first found in egg
  • PC=PA + Choline
  • the most abundant phospholipid
  • storage for choline (essentially dietary nutrient)
  • major component of lung surfactant (DPPC)
131
Q

Describe the general structure and most important functions of PE

A
  • cephalin (neuronal tissue)
  • PE=PA + ethanolamine
  • the second most abundant phospholipid
  • used for the synthsis of PS in exchange reaction with free serine
132
Q

Describe the general structure and most important functions of PS

A
  • PS=PA + serine
  • inner leaflet of the plasma membrane
  • required for membrane synthesis
  • recognition of apoptotic cells
133
Q

Describe the general structure and most important functions of Pl

A
  • Pl=PA + inositol
  • unusual lipid: contains stearin acid at C1 and arachidonic acid at C2
  • reservoir of arachidonic acid
  • precursor for prostaglandins
  • OH groups can be phosphorylated to produce second messenger PIP2
  • PIP2 is a substrate for PLC to produce IP3 and DAG
  • serve as anchor points
134
Q

Describe the general structure and most important functions of PG

A
  • PG=PA + glycerol
  • A precursor of surfactant
  • precursor for the synthesis of cardiolipin
135
Q

Describe the general structure and most important functions of cardiolipin

A
  • diphosphatidylglycerol
  • 2 PA molecules esterified through their phosphate groups
  • exclusive to the inner mitochondrial membrane
  • maintains the structure and function of ETC complexes
  • maintains proton gradients
136
Q

Describe the general structure and most important functions of plasmalogen

A
  • Ether glycerophospholipid
  • FA at C-1 attached via ETHER linkage
  • unsaturated FA at c-1
  • phosphatidALcholine in heart muscles
  • phosphatidALethanolamine in nerve tissue
137
Q

Describe the general structure and most important functions of PAF

A
  • ether glycerophospholipid
  • FA at C-1 attached eithe ETHER linkage
  • saturated FA at C-1 and a short acetyl group at C-2 rather than acyl
  • synthesized and released by variety cell types
  • one of the most potent bioactive molecules: thrombotic and inflammatory response
  • mediate anaphylaxis and hypersensitivity
138
Q

Describe the general structure and most important functions of sphingomyelin

A
  • SM
  • MOST ABUNDANT
  • SM=ceramide + phosphocholine
  • predominant sphingophospholipid in mammalian cells
  • major structural spingolipid in the plasma membrane.
    • role in lipid raft formation
    • role in signaling as precursor for the bioactive ceramide
  • abundant in nerve tissues (myelin sheath)
139
Q

Describe the general structure and most important functions of ceramide

A
  • FA that is attached to glycerol is what makes Cer and SM different
  • Cer=sphingosine + FA
  • differ in the type of FA attached to sphingosine
  • precursor for SM and all glycosphingolipids
  • bioactive second messenger
  • maintain skin’s water-permeability barrier
  • decreased levels are associated of skin diseases
140
Q

Describe the general structure and most important functions of sphingosine

A
  • sphingosine =palmitic acid + serine
  • bioactive second messenger molecule
  • precursor for sphingosine 1-phosphate
  • controls endocytosis of rhodopsin and another light sensitive eye protein, the transient receptor potential (TRP) channel
141
Q

Describe the general structure and most important functions of shingosine 1-phosphate

A
  • shingosine is a presurosor for it.

- potent bioactive second messenger recognized by at least 5 different GPCR

142
Q

Describe the general structure and most important functions of cerbrosides

A
  • neutral GSLs
  • cerebroside=ceramide + sugar
    - galactosylceramide via a glycosidic link
  • essential components of membranes, mostly found on the outer leaflet of the plasma membrane
  • participate in lipid rafts
  • predominant in nerve tissue (brain and periphery)
143
Q

Describe the general structure and most important functions of gangliosides

A
  • acidic GSL
  • negatively charged at pH 7
  • found in ganglion cells in the CNS
  • sulfatides=galactocerebrosides + SO3- group found in brain and kidney
144
Q

Explain the etiology of sphingolipids, what enzyme is deficective in each disease and what are the consequences of the deficiency

A

Acid hydrolase defect

  • SL substrate accumulates
  • affects nervous tissue
  • may be fatal
  • genetic variability
  • low incidence
145
Q

Tay-Sachs disease

A
  • sphingolipidoses
  • hexosaminidase A deficient
  • gangliosides accumulate
  • blindness
146
Q

Niemann-pick disease

A
  • sphingolipidoses
  • sphingomyelinase deficient
  • sphingomyelin accumulates
147
Q

Gaucher’s disease

A
  • sphingolipidoses
  • B-glucosidase deficient
  • glucosylceramide accumulates
148
Q

Sphingolipidoses in general

A

Lisosomes—acidic hydrolase, accumulation of substrate

149
Q

List sphingolipidoses that are characterized with blindness and/or cherry red spots

A
  • Tay-Sachs (gangliosides)
  • Sandhoff (similar to TS)
  • Niemann Pick (A&B)
150
Q

Sphingolipidid in the eye

A
  • normal tensive
  • absent in hypertensive Aq humor
  • increased IOP/glaucoma
151
Q

Describe the structure of steroids, sterols, cholesterol, bile acids, and bile salts, and be able to identify the shared components

A
  • ABCD ring (sterol nucleus)

- acetyl CoA makes the ring

152
Q

Explain the structure and functions of free and esterified cholesterol

A

Free cholesterol
-found in membranes of all animal cell membranes

Esterified cholesterol

  • not found in membranes
  • most of the plasma cholesterol is in this form
153
Q

Identify the central organ for cholesterol metabolism

A

Liver

154
Q

Discuss the origin of gall stones and know the possible causes for their formation

A

Too much cholesterol causes gall stones
-too little bile salt

Possible causes

  • inefficient enterohepatic cycling of bile salts
  • liver dysfunction
  • other idiopathic reason
155
Q

Describe the size, density, composition and functions of lipoproteins present in plasma: the chylomicrons, VLDL, remnant particles, low density lipoproteins and high density lipoproteins

A

Chylomicrons:
-size vary depending on the meal content, but in general they are the largest in size, least dense, and contain the highest percentage of fat. Produced by gut cells

VLDL:
-very similar to chylomicrons but produced by hepatocytes, smaller and more dense, containing a high percentage of fat reflecting their primary role to distribute fay away from the liver or peripheral tissues (more phospholipids)

LDLs:

  • highest percentage of cholesterol, reflecting their role to distribute cholesterol to tissue expressing the LDL receptor
  • produced from VLDL via lipolysis in the bloodstream.
  • Bad cholesterol

HDLs

  • smaller and denser
  • contain the highest percentage of proline, reflective of one of the roles (reservoir of lipoproteins)
  • second largest percentage of cholesterol
  • good cholesterol
156
Q

Explain why accurate plasma lipid profiles require blood collection and further analysis in fasted patient.

A
  • the size and density of the lipoproteins are routinely used in plasma lipid profiling as part of the separation process
  • accurate profiles require blood collection and further analyses in fasted patients
157
Q

Describe the cell types and sites for synthesis of chylomicrons and outline the general steps in their assembly

A

Chylomicrons

  • formed in the ER and Golgi of intestinal mucosal cells using Apo B-48
  • MTP transfers lipids to ApoB-48
  • Nascent chylomicrons are excreted through the plasma membrane into the lymph
  • from lymph they enter blood stream where they undo modifications and acquire additional Apo-es from HDL
  • peripheral calls expressing LPL hydrolyze TAGs to FA and glycerol
  • remaining is cleared form the blood stream by the liver
158
Q

Describe the cell types and sites for synthesis of VLDL and outline the general steps in their assembly

A
  • assembled in the ER and golgi of liver cells . Full length Apo B-100
  • VLDL are directly secreted into the blood stream, acquire APO C-II and Apo E from HDLs
  • LPL hydrolyzes VLDLs and TAGs
  • VLDVL decrease in size and becomes denser
  • Apo B-100 remaining in the LDL is a ligand recognized by the LDL receptors on the surface of cells and taken up via endocytosis in the lysosomes acid hydrolysis break down lipids
159
Q

Describe the cell types and sites for synthesis of HDL and outline the general steps in their assembly

A
  • reverse cholesterol transport: the effluent of cholesterol from peripheral tissues to HDL
  • HDLs are considered good, however the ratio to LDL is usually considered
  • APO A-1 produced in liver and intestinal cells and secreted in the circulation as free apolipoprotein
  • interacts with ABCA1 transporter that transfers phospholipids and cholesterol from peripheral cells to lipid poor Apo A-1
  • converted to discoidal particles
  • reservoir of Apo CII and Apo E
  • HDL particles are not taken up by the liver but instead they transfer cholesteryl eters from the HDL to the liver via CETP
160
Q

Discuss the main component processes of atherogensis-oxidized LDL, endothelial dysfunction, arterial deposition of lipids, chronic low grade inflammation and outline the risk factors for increases LDL modification

A

Oversupply of cholesterol:

  • inhibit de novo synthesis of cholesterol
  • inhibit expression of LDLR. Decreased LDL uptake
  • activate ACAT to produce more CE
  • atherosclerosis

Factors increasing the propensity for producing modified LDL in circulation

  • high blood sugar
  • oxidative stress
  • chemicals present in tobacco smoke
    • smokers and diabetics will have an increased risk of cardiovascular disease
    • some protective effect can come from antioxidants (E,C,A)
161
Q

Abetalipoproteinemia (Bassein-Kornzweig syndrome)

A
  • defects in the microsomal transfer protein (MTP)

- progressive degeneration of the retinue that can progress to near blindness (due to deficiency of vitamin A, retinol)

162
Q

Cortisol function

A

Normal: stress hormone, increase GNG, anti inflammatory, muscle protein breakdown, immune response

Too much
-cushing syndrome (obesity, moon face)

163
Q

Aldosterone functions

A

Normal: renal reabsorption of Na+ and excretion of K+

Too much
-increased Na+, decreased K+

Too little
-decreased Na+, increased K+,
Large sodium loss in urine, hypotension

164
Q

Testosterone function

A

normal
-promote male development

Too much
-masculinization of females

Too little
-feminization of males

165
Q

Estrogens functions

A

Normal

-promote female development

166
Q

Describe the mechanisms by which glycogen synthesis and degradation are counter regulated wot meet the needs of the body as a whole (hormonal regulation)

A

2 regulatory enzymes: glycogen phosphorylase and glycogen synthase

Glycogenolysis activated

  • blood glucose drops
  • activated in muscle and liver

Why glycogenesis activated

  • muscle—when resting and fed
  • liver—when fed

Biochem BLOCK 2 (14 decks)

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