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LECOM DSP Biochemistry 2022 > Section V (Chapters 30-33) > Flashcards

Section V (Chapters 30-33) Flashcards

1
Q

What is the overall importance of fatty acids as fuels?

A

Due to reduced structure, FA allow for optimal oxidation/fuel production via beta-oxidation

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2
Q

How does fatty acids transport into mitochondria?

A

Long chain FA become activated by actyl CoA synthetase (thiokinase), which cleaves the beta-bond of ATP for oxidation
From there, FA enters mitochondria via facilitated diffusion, getting linked to carnitine by CPTI through the inner membrane via translocase

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3
Q

What inhibits CPT1?

A

Malonyl-CoA

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4
Q

What is the importance of carnitine in fatty acid metabolism?

A
  • Serves as carrier to transport activated fatty acyl groups into inner mitochondrial membrane
  • Transporters transport these into mitochondria
  • Obtained from diet or synthesized from side chain of lysine, begins in muscle and is completed in liver
  • Stored in skeletal muscle
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5
Q

What is the process of beta-oxidation? Where does it occur?

A

In mitochondrial matrix
4 steps:
(1) Trans double bond form between α and β-C => FADH2
(2) H2O is added, H to α & OH to β-carbon
(3) β-carbon is oxidized to keto group by hydroxyl group of β-carbon => NADH
(4) Cleavage of 2-C acetyl-CoA unit

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6
Q

How many ATPs are produced by the completed oxidation of palmitate via B-oxidation?

A

Palmitate (16C) = 8 acetyl-CoA + 7 NADH + 7FADH2 = 8(10 ATP) + 7(2.5 ATP) +7(1.5 ATP) -2 = 106 ATP
The -2 stands for activation of palmitic acid to palmitoyl CoA

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7
Q

Fed state hormonal & allosteric controls over fatty acids

A

Insulin activates acetyl-CoA carboxylase which converts acetyl CoA => malonyl-CoA to inhibit CPTI preventing fatty acyl transport into mitochondrial matrix

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8
Q

Fasting state hormonal & allosteric controls over fatty acids

A

Glucagon activates lipolysis => triacylglycerides are released to be oxidized

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9
Q

What occurs when there is an increased energy demand?

A

↑AMP which activates AMPK that inactivates acetyl-CoA carboxylase =↓malonyl-CoA => CPTI activated for FA oxidation

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10
Q

What occurs when there is high energy present?

A

High energy (ATP/ADP ratio high) slows down ETC, which results in excess of NADH or FAD2H, inhibiting oxidation of fatty acids

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11
Q

What additional step is needed for unsaturated fat?

A

Need isomerase & NADPH-reductase to convert cis-trans double bond

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12
Q

What additional step is needed odd fatty chain?

A

Need vitaminB12 to turn propionyl-CoA => succinyl-CoA

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13
Q

What additional step is needed for very-long chain?

A

Exclusively oxidized in peroxisomes by β-α oxidation:
- Step 1: oxidase = generate H2O2, remaining 3 are same as β-oxidation => 1 NADH & acetyl-CoA per turn until a 4-6 carbon chain remains & get sent to mt to finish up

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14
Q

What additional step is needed for long-chain branched fatty acids?

A

Also oxidized in peroxisome to 8C chain and sent to mt

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15
Q

What is Zellweger syndrome?

A

Due to defective peroxisomal biogenesis = elevated long-chain FA in plasma = complex developmental/metabolic phenotypes

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16
Q

What is Refsum disease?

A

Caused by defect in a specific enzyme (phytanoyl coenzyme A hydroxylase) for phytanic acid (diet) metabolism, thus builds up, improved with decreasing in diet

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17
Q

What is ω-oxidation?

A

Oxidation of terminal methyl group in ER

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18
Q

What occurs in ω-oxidation?

A

ω-carbon is oxidized to alcohol by cytochrome P450/oxygen/NADPH => dehydrated to dicarboxylic acid by dehydrogenase=> β-oxidation forming 6-10 carbon chains that are water soluble and enter blood => can be further oxidized or excreted in urine

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19
Q

What can speed up ω-oxidation?

A

↑substrate concentration/defect in β-oxidation increase the rate of this process

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20
Q

How are ketone bodies formed in the liver, and utilized by extra hepatic tissues?

A

2 acetyl-CoA react by enzyme thiolase => acetoacetyl CoA (release Co-ASH) react with HMG-CoA synthase and third acetyl CoA => (release Co-ASH) HMG-CoA reacts with HMG CoA lyase => (release Acetyl CoA) acetoacetate => conversion to β-hydroxybutyrate by dehydrogenase or spontaneously to acetone
Acetoacetate/β-hydroxybutyrate => tissue => convert to acetyl-CoA and oxidize in TCA

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21
Q

What is the regulation mechanism for ketogenesis?

A

Glucagon activates β-oxidation due to ↑ NADH/NAD+ ratio which diverts acetyl-CoA away from TCA & towards ketogenesis; NADH also divert oxaloacetate => malate => gluconeogenesis

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22
Q

What is ketosis? Why are children more prone to ketosis?

A

State of elevated ketone bodies in body tissues; children are more prone to ketosis than adults because their bodies enter the fasting state more rapidly by using more energy

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23
Q

What is the occurrence of diabetic ketoacidosis in patients with Type 1 diabetes?

A

DKA results from a high glucagon: insulin ratio (insulin not being secreted so high blood glucose too) => ketogenesis in liver = elevated KB; metabolic stress caused by EPI/cortisol release = elevate blood glucose levels; hyperosmolarity of blood => diuresis, metabolic acidosis, CNS dysfunction/coma and death if untreated

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24
Q

What is the molecular pathology & clinical manifestation of MCAD?

A

MCAD deficiency results from mutated dehydrogenase that prevent medium-chain FA oxidation; sx include hypoketotic hypoglycemia when fasting (prevents full oxidation from occurring)

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25
Q

What occurs in hypoglycin exposure (Jamaican vomiting disease)?

A

Hypoglycin exposure inhibits acetyl-CoA dehydrogenase, first enzyme in β-oxidation to activate FA; leads to severe hypoglycemia & death (prevents oxidation from even starting)

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26
Q

What are the causes of carnitine deficiencies?

A
  • liver disease resulting in decreased synthesis of carnitine
  • malnutrition or strictly vegetarian diets
  • increased requirement for carnitine (pregnancy, severe infections, burns, or trauma)
  • hemodialysis, which removes carnitine from the blood
    congenital deficiencies in renal tubular reabsorption of carnitine
  • congenital deficiencies in carnitine uptake by cells
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27
Q

What does carnitine deficiency impact?

A

Affects the liver, where an inability to oxidize fatty acids impairs gluconeogenesis during a fast, leading to severe hypoglycemia, coma, and death. CPT-II deficiency occurs primarily in cardiac and skeletal muscle, where symptoms of carnitine deficiency range from cardiomyopathy to muscle weakness with myoglobinemia following prolonged exercise

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28
Q

What is the treatment for carnitine diseases?

A

Supplementation with carnitine

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29
Q

Who does MCAD commonly occur in?

A

1/4,000 Northern Europeans and between 1/13,000 and 1/26,000 of the general public.

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30
Q

MCAD is an autosomal … genetic disease

A

Recessive

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31
Q

What has been associated with MCAD deficiency?

A

SCID

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32
Q

What is non-ketotic hypoglycemia?

A

Results because after fasting has depleted the glycogen in the liver, the liver depends on ATP generated by fatty acid oxidation to provide the energy for gluconeogenesis. Therefore no β-oxidation, no gluconeogenesis with resulting severe hypoglycemia.

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33
Q

What are the carbon sources for fatty acid synthesis?

A

Fed state = FA synthesis in liver (>adipose tissue) with dietary carb/proteins: glucose or AA that can covert to pyruvate which is converted to acetyl-CoA and oxaloacetate, then to citrate = building block for FA by FA synthase complex

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34
Q

What is the role of acetyl CoA in FA synthesis?

A

Precursor for citrate via conversion of acetyl CoA & oxaloacetate

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35
Q

What are the metabolic NADPH sources for FA synthesis?

A

NADPH (from pentose phosphate pathway & oxaloacetate recycling) is used by FA synthase complex to reduce rxns
Oxaloacetate recycling is conversion to malate by malate dehydrogenase (NAD+) then oxidation and decarboxylation by malate dehydrogenase/malic enzyme (NADP+)

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36
Q

What is the role of acetyl-CoA carboxylase in FA synthesis?

A

Acetyl-CoA carboxylase convert acetyl-CoA to malonyl-CoA, which adds to growing FA chain; regulated by phosphorylation/inactivated (AMPK), dephosphorylation/activated (insulin), allosteric activation (citrate) or inactivation (palmitoyl-CoA), & induction and repression of its synthesis

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37
Q

What is required for acetyl-CoA carboxylase?

A

Biotin, ATP, and CO2

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38
Q

What is the structure & function of FA synthesis?

A

2 identical subunits, each with acyl carrier protein (ACP) with free SH-group which acts to condense acetyl & malonyl moieties => 5C keto group that is then reduced to form double-bond (repeated until 16 long =palmitate) 2 NADPH required as the reducing equivalents

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39
Q

What will be effected with carnitine deficiency?

A

Carnitine is required for FA oxidation = decreased fatty acid oxidation and gluconeogensis in fasting state

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40
Q

What will be effected with biotin deficiency?

A

Acetyl-CoA carboxylase requires biotin = unrestricted FA oxidation because no malonyl CoA preventing carnitine uptake into mitochondria for oxidation; also slower synthesis because less malonyl to give carbon

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41
Q

What will be effected with pantothenic acid deficiency?

A

Pantothenic acid is a precursor to coenzyme A (CoA) & FA synthase = prevents fatty acid elongation and synthesis

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42
Q

What is required for desaturation of FAs?

A

requires O2, NADH and cytochrome b5

43
Q

Where does desaturation of FAs occur?

A

In endoplasmic reticulum

44
Q

Why are some desaturated fatty acids essential?

A

Desaturated FA, such as linoleic acid, must come from DIET; desaturated FA are required for synthesis of arachidonic acid/prostaglandins and eicosanoids, skin’s impermeability to water and neuronal FA

45
Q

What are eicosanoids?

A

Eicosanoids (prostaglandins, thromboxanes & leukotrienes) are biologically active lipids that act as regulators of cellular fxn, they are derived from polyunsaturated FA which are either synthesized or obtained from diet (linoleic acid- plant oils)

46
Q

How is arachidonic acid released from membrane lipids?

A

Arachidonic acid is released from membrane by activated phospholipase A2/C when histamine or cytokines interact with membrane receptor

47
Q

What is the structure of prostaglandins?

A

20C, internal 5C-ring, with varying substituents; un-clot & dilate

48
Q

What is the structure of thromboxanes?

A

5C-ring w/ 1O; clot and constrict

49
Q

What is the role of leukotrienes?

A

Activated during inflammation

50
Q

Roles of cyclo-oxygenase

A

Arachidonic acid to PGG (PGG to PGH by peroxidase, then to TXA by TXA synthase)

51
Q

Roles of lipoxygenase

A

Lipoxygenase => leukotrienes (LT-C/D => bronchoconstriction)

52
Q

Roles of phospholipase A2

A

Activated by histamine or cytokines, activates phospholipase C and other lipases to release arachidonic acid

53
Q

What are the functions of COX-1 & COX-2 isozymes?

A

COX-1 = normal PG/TXA synthesis, found in most tissues
COX-2 = induced by inflammation, regulated by cytokines and growth factors
NSAIDs inhibit both COX = side effects such as GI and antiplatelet effects
COX-2 inhibitors = potent anti-inflammatory, less side effects – can effect cardiovascular

54
Q

What is the use of aspirin in acute myocardial infarction reduction risk?

A

Low dose aspirin covalently aceylates active site of cyclooxygenase and blocks TXA (thromboxanes) production from arachidonic acid= less clotting = protective against MI

55
Q

What gives rise to thromboxane A3, and the health benefit that this provides. (TXA3 causes less clotting than TXA2)

A

Fish oils & omega 3-fatty acids

56
Q

What is the role of VLDL?

A

TG is packed with cholesterol, phospholipids and proteins (apo100) to form VLDL
Includes MTP protein

57
Q

Synthesis of triglyceride molecules in liver - how does it occur?

A

Glycerol-3-P + fatty acyl-CoA=>phosphatidic acid=>DAG =>TG, transport by VLDL into the blood, where TG are cleaved by LPL forming fatty acids and glycerol, generating IDL => LDL

58
Q

Effects of insulin & glucagon on triglyceride handling in adipose tissue

A

Elevated insulin/glucagon levels causes LPL synthesis by adipocytes = cleave VLDL/chylomicrons to obtain FA and store it as TG; insulin also causes conversion of glucose => glycerol-3-P => TG synthesis

59
Q

Identify the major structural components and primary biological functions of glycerophospholipids and sphingolipids

A

FA are precursors to glycerophospholipids and sphingolipids, which are both major components of cellular membranes
Glycerophopholipids are also components of blood lipoprotein, bile and surfactant
Sphingomyelin form myelin sheath around neurons in CNS, serve in intercellular communication, ABO-blood typing, membrane receptors for virus/toxins

60
Q

What is the biological importance of phospholipase A2?

A

PLA2 releases arachidonic acid from membrane, degrades glycerophospholipids, and repairs membrane lipids from ROS damage by recognizing/removing distortion

61
Q

What is the biological importance of phospholipase C?

A

PLC also release arachidonic acid from the membrane along with DAG; PLC cleaves PIP2 into secondary messengers DAG and IP3

62
Q

Importance of phosphatidylcholine in development of lung surfactant of newborns?

A

Phosphatidylcholine (lecithin) concentration is monitored prior to delivery to prevent RDS, because surfactant decreases the tension in the alveoli = prevent lung collapse

63
Q

What is an independent factor for myocardial infarctions and strokes, insulin resistance and type 2 diabetes mellitus, hypertension, and gallbladder disease?

A

Obesity

64
Q

What is metabolic syndrome? How is it diagnosed?

A

Metabolic syndrome dx is made by at least 3 of the following: increased waist size, elevated TG, reduced HDL, HTN or elevated fasting glucose; essentially someone with obesity, insulin resistance and altered blood lipid levels has metabolic syndrome
Metabolic syndrome = cluster of a variety of metabolic abnormalities that together increase risk of DM-II and CVD

65
Q

Most alcohol metabolism occurs via

A

Alcohol dehydrogenase (ADH)

66
Q

What occurs with alcohol dehydrogenase?

A

ADH (cytosol) => acetaldehyde (toxic) converted with ALDH (mt) => acetate + NADH
Acetate can be activated to acetyl-CoA and enter TCA or FA synthesis
Also reduces NAD+ to NADH

67
Q

What occurs in the microsomal ethanol oxidizing system?

A

MEOS (ER, cP450:CYP2E1) => acetaldehyde; requires NADPH and O2

68
Q

How do enzymes alter the rate & route of ethanol metabolism?

A

ADH, ALDH & CYP2E1 exist in variants in different individuals = different tolerance and susceptibility to development of disease

69
Q

What are the changes for an allelic variant of ADH?

A

ADH1 (liver)= highest specificity/lowest Km for EtOH; ADH1B*2 variant has very ↑Vmax

70
Q

What are the changes for an allelic variant of ALDH?

A

ALDH2 (liver) (low Km & high Vmax) > ALDH2*2 variant (↑Km & Vmax↓) decrease alcoholism but can increase the effects of acetaldehyde levels

71
Q

How is energy gained from the metabolism of alcohol?

A

In liver: Acetate reacts with Acetyl-CoA Synthetase I=>cytosolic acetyl-CoA=>cholesterol/FA synthesis
Other tissues (heart/sk.m): Acetate reacts with ACSII=> mitochondrial acetyl-CoA => TCA

72
Q

Products of alcohol metabolism impact on NADH

A

inhibit FA oxidation=hyperlipidemia=>fatty liver/steatosis), inhibit TCA=ketosis, lactic acidosis =>↑uric acid =gout/hyperuricemia, inhibit gluconeogenesis=hypoglycemia

73
Q

Products of alcohol metabolism impact on acetaldehyde

A

adduct formation by rxn w/ AA, sulfhydryl, nucleotides, and phospholipids = hepatitis due to diminished protein secretion and influx of water; inhibit glutathione

74
Q

Products of alcohol metabolism impact on free radicals

A

hydoxyethyl radical is produced during metabolism of ethanol by CYP2E1 and cytochrome P450 system, increased by acetaldehyde adducts
Targets phospholipids for peroxidation which can inhibit ETC or uncouple, leading to inflammation and necrosis

75
Q

What are the changes associated with hepatic cirrhosis?

A

Hepatomegaly/fatty/fibrosis => loss fxn = shrunken/cirrhotic; ↑NH4+ level & jaundice

76
Q

Acute problems of alcohol consumption

A

inhibit FA oxidation and cause hyperlipidemia, inhibit gluconeogenesis and cause ketoacidosis because body using acetate for energy

77
Q

Chronic problems of alcohol consumption

A

Fatty liver/hepatic steatosis, hepatitis, fibrosis & cirrhosis

78
Q

What are the sources of cholesterol?

A

Obtained from diet or synthesized in the cytosol
Made in liver, intestine, adrenal cortex

79
Q

What is the function & purpose of cholesterol?

A

Cholesterol regulates membrane fluidity
Cholesterol is a precursor for steroid hormone synthesis, bile salts, and vit. D

80
Q

Cholesterol is … and … must be transported within …

A

Hydrophobic, insoluble, lipoproteins

81
Q

What is the role of VLDL?

A

very low density lipoprotein: made in liver, packaged form of triacylglycerols and cholesterol. VLDL travels to bloodstream to deliver TG
TG cleaved from VLDL, leaving VLDL remnants → becomes LDL

82
Q

What is the role of LDL?

A

low density lipoprotein: taken back to liver, taken to adrenocortical and gonadal tissue for steroid hormone synthesis
Remaining LDL → macrophage degradation → foam cells in blood vessels → cascade of atherosclerosis

83
Q

What is the role of HDL?

A

remove cholesterol from blood and returns it to the liver

84
Q

What is the function of LCAT?

A

LCAT reaction; lecithin:cholesterol acetyltransferase reaction
HDL process of converting cholesterol → cholesterol ethers
Catalyzes conversion of HDL3 (less protective against atherosclerosis) to HDL2 (more protective against atherosclerosis)

85
Q

What is the function of CETP?

A

Cholesterol Ester Transport Protein: takes HDL Cholesterol/cholesterol esters either back to liver or to other lipoproteins

86
Q

What is the function of ACAT?

A

acyl-CoA-Cholesterol acyl transferase: catalyzes cholesterol ester production

87
Q

What is an associated problem with cholesterol levels?

A

Elevated levels of LDL are associated with formation of atherosclerotic plaques, can occlude blood vessels → heart attack and stroke

88
Q

What is HDL2?

A

HDL2: more protective against atherosclerosis

89
Q

What is HDL3?

A

HDL3: less protective against atherosclerosis

90
Q

What is significant in the ratio of HDL2 & HDL3?

A

HDL3 has more triacylglycerol than HDL2, less capable of removing from blood

91
Q

How may LDL-R be down-regulated at the cell surface?

A

LDL-Receptor: located primarily in the liver: their number is regulated by cholesterol content in hepatocytes
High dietary cholesterol → low LDL receptors → plasma LDL rises
Converse is true with drugs to lower LDL

92
Q

What are the stages of cholesterol synthesis?

A

Stage 1: Acetyl CoA → mevalonate
Stage 2: Mevalonate → 2 Isoprenes
Stage 3: Condensation to squalene
Stage 4: squalene → steroid nucleus
HMG-CoA reductase is rate limiting enzyme of biosynthesis, regulated by: transcriptional regulation, proteolysis (regulated amount of enzyme) nad covalent modification)

93
Q

What is the fate of cholesterol after its synthesis?

A

Cholesterol not used for synthesis of membranes, steroid hormones, or vit. D are stored in the liver for later use
Liver-stored cholesterol is also a source of cholesterol for bile salt synthesis

94
Q

What are the bile salts?

A

Bile salts: ad in digestion of lipids by forming micelles
2 sets of bile salts:
Cholate series: 3 hydroxyl groups on base cholesterol
Chenodeoxycholate series: 2 hydroxyl groups on base cholesterol

95
Q

What is the rate-limiting enzyme for bile salt formation?

A

7α-hydroxylase

96
Q

What does statins inhibit?

A

HMG-CoA reductase

97
Q

What does bile acid resins do for cholesterol levels?

A

Increase fecal excretion of bile salts

98
Q

What is the mechanism of action for niacin?

A

Activates LPL
Reduces hepatic production of VLDL
Reduces catabolism of HDL

99
Q

What is the mechanism of action for fibrates?

A

Antagonizes the transcription factor PPAR-alpha, causing an increase in LPL activity; a decrease in apolipoprotein CIII production, and an increase in apolipoprotein AI production

100
Q

What is the mechanism of action for ezetimibe?

A

Reduces intestinal absorption of free cholesterol from the gut lumen

101
Q

What is traditionally increased in cholesterol-related therapeutics?

A

HDL

102
Q

What is traditionally decreased in cholesterol-related therapeutics?

A

LDL

103
Q

What drug reduces the most cholesterol level?

A

Statins

LECOM DSP Biochemistry 2022 (11 decks)

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