Metabolism Flashcards
ATP, TCA, Glycolysis, Oxidative Phosphorylation, Fatty acid synthesis (219 cards)
1
Q
cellular location of cholesterol synthesis
A
cytosol with some enzymes bound to membrane of ER
2
Q
the function cytosolic glycerophosphate dehydrogenase
A
used with glycerophosphate shuttle Accepts 2 e from NADH and transfer them to dihydroxyacetone phosphate DHAP (Cytosol) DHAP converts back to glycerol-3-phosphate FADH2 is produced (matrix)
3
Q
The impact of decreased activity of G6Pase on Pyruvate and glucose
A
red. G –> hypoglycemia
inc. pyr –> lactic acidosis
4
Q
Addition of a two-carbon unit to an acetyl group on fatty acid synthase:
- ACP
- FA synthase
- Condensation B-ketoacyl formation
A
- First, an acetyl moiety is transferred from acetyl CoA to the Acyl-Carrier Protein (ACP)
- The malonyl group attaches to the phosphopantetheinyl residue of the ACP of the FA synthase
- The acetyl group condenses with the malonyl group
- CO2 is released and
- a 3-ketoacyl group is formed
5
Q
Enolase inhibitor
(inhibition of substate level phosphorylation)
A
Fluoride inhibits enolase resulting in a decrease in ATP synthesis
Note: Blood samples for glucose quantification are collected in tubes containing fluoride.
6
Q
The enzyme that catalyzes the last TCA rxn
A
malate dehydrogenase
malate + NAD+ → OAA + NADH + H+
»Oxaloacetate is also produced by:
˃Transamination of Asp
˃Carboxylation of pyruvate
»Oxaloacetate is recycled in TCA cycle
7
Q
The conformational change of this ATPsynthase allows the synthesis of ATP
A
passing of the protons through F0 channel in the ATP Synthase Complex
8
Q
Status of [HMG-CoA Reductase_p]
A
inactive (promoted by glycogen)
9
Q
The effect of glucagon on the short-term regulation of HMG-CoA Reductase
A
Insulin activates phosphatase Phosphatase dephosphorylate the [HMG-CoA Reductase_p] and makes it active [HMG-CoA Reductase_X] is active
10
Q
the effect of insulin on hormone sensitive lipase
A
inhibition
11
Q
The effect of acetyl CoA concentration on pyruvate carboxylase
A
When Acetyl Co-A is high –> pyruvate carboxylase is activated
12
Q
the effect of low cholesterol on transcription of HMG-CoA reductase
A
1- SCAP-SREP translocation from ER to Golgi (movement) 2- Cleaved by S1P and S2P proteases (liberation) 3- SREP translocates to the nucleus and activates transcription. movement, liberation, translocation, activation
13
Q
List the mitochondrial dehydrogenases that donate electrons to Co-Q
A
From ETC- Both complex I and II ( I is NADH dehydrogenase and II is succinate dehydrogenase) Glycerophosphate dehydrogenase (glycerophosphate shuttle) Acetyl CoA dehydrogenase
14
Q
A mitochondrial disorder, leads to lactic acidemia, developmental delay, seizure, extraocular palsies, hypotonia and ultimately death by the age of 2 years
A
Leigh disease
15
Q
The major cause of congenital lactic acedemia
A
Pyruvate dehydrogenase deficiency
16
Q
The malfunctioning of these two ATP transporters of mitochondrial leads to necrotic cell death
A
ANT and VDAC
17
Q
major sites of de novo cholesterol synthesis
A
Most tissues are capable of cholesterol formation but the major de novo synthesis takes place in: liver intestine adrenal cortex and reproductive tissues
18
Q
Patients with this disorder suffer from early progressive liver failure and neurologic abnormalities, hypoglycemia and increased lactate in the body fluids. The also have reduced levels of ETC complexes ( I, II, II, IV) due to reduction in synthesis.
A
Fatal Infantile Mitochondrial Myopathy
19
Q
Gluconeogenesis key reactions
A
20
Q
Lactate dehydrogenase deficiency
A
Deficiency of lactate dehydrogenase leads to muscle cramping and myoglobinuria after intense exercise (LDH M isoform childhood-onset)
21
Q
Increased [F-2,6-BP] causes:
A
Inhibition of gluconeogenesis
Activation of:
Glycogenesis
Glycolysis, and
Lipogenesis
22
Q
the rxn catalyzed by G3PDH
and the inhibitor of G3PDH
A
Phosphorylation of GAP using Pi*
•Glyceraldehyde 3-phosphate dehydrogenase (G3PDH), with NAD+ as a cofactor, catalyzes the phosphorylation of GAP yielding:
•1,3-BPG, and
•NADH*
Arsenate inhibits glyceraldehyde 3-P dehydrogenase (competes with Pi for the active site)
23
Q
amino acid degradation as anaplerotic rxns of TCA
A
»Degradation of amino acids
˃Oxaloacetate from Asp
˃a-ketoglutarate from Glu
˃Succinyl CoA from
+Val and Ile in all tissues except liver
+ Met, Thr, and odd-chain FAs
24
Q
Pyruvate kinase deficiency
A
Deficiency in pyruvate kinase, an autosomal recessive trait, causes a decrease in ATP production leading to the disturbance in the cell membrane gradient and loss of ions and water causing the RBCs to contract, crenulate, and die (nonspherocytic hemolytic anemia- dead RBC). The resulting accumulation of 2,3-diphosphoglycerate (2,3-DPG) shifts the Hb-O2 dissociation curve to the right.
Inc. 2,3-DPG
25
The status of glycerophosphate shuttle when the cytosolic NADH/NAD is lower than in mitochondria
Active **regardless**
**Active even** when the cytosolic NADH/NAD+ is low
26
un form of lipoprotein from the liver
VLDL
27
3 ways to produce oxaloacetate
1. TCA-malate dehydrogenase (last step: malate --\> OAA)
2. ASP transamination
3. Pyruvate carboxylation
28
inhibits glucokinase
F6P
29
The enzymes necessary for gluconeogenesis from glycerol
(glycerol is a minor source)
1. **Hormone sensitive lipase**- makes glycerol
2. **Glycerol kinase**- makes glycerol 3 phosphate
3. **Gycerol 3P dehydrogenase**- makes DHAP from G3P
30
The effect of increased [F2,6-bisP] on glycolysis (in muscle)
* In the muscle, PFK-2 is:
* Activated by↑[AMP] and ↑[norepinephrine] resulting in increased [F2,6-bisP] → activation of glycolysis → ATP synthesis for muscle contraction.
* The allosteric effecter F-2,6-BP is synthesized in a reaction catalysized by phosphofructokinase-2 (PFK-2):
F6P → F2,6-bisP
31
Relative affinity of HbF and HbA to 2,3-BPG
**HbF has a lower** affinity for 2,3-BPG than does HbA. Consequently HbF has a higher affinity for O2, which facilitates the unloading of O2 at the maternal-fetal interface
32
Elongation of fa synthesis
* Activated palmitate can be elongated two carbons at a time in the ER
* Malonyl CoA donates the two-carbon units
* NADPH provides the reducing power
* The major elongation is
Palmitoyl-CoA (C16) → Stearyl-CoA (C18)
•Very long-chain FAs (C22 → C24) occur especially in the brain
33
Gluconeogenesis importance
Source of glucose between meals
Between meals, glucose is released via **glycogenolysis**
nWhen the liver stores are depleted, gluconeogenesis is essential for survival during:
Sleep
Long term fasting, or
Starvation
Gluconeogenesis is the synthesis of glucose de novo
using noncarbohydrate sources
34
The active and inactive forms of HMG-CoA reductase
[HMG-CoA Reductase\_p] active (Glucagon and amp-activated PKK) [HMG-CoA Reductase\_X] inactive (Insulin and phosphatase)
35
•Fatty Acid Synthase (FAS)
* Cytoplasmic multifunctional enzyme
* The growing chain of FA is attached to Acyl-Carrier Protein (ACP) of FAS
* The addition of each two-carbon unit is followed by two reduction reactions using NADPH
36
both NADPH and NADH require this vitamin
Niacin
37
fa desaturation
linoleic desaturation
* The produced fatty acids will be used to synthesize several compounds such as:
* components of complex lipids of biological membranes
* Desaturation occurs in the ER and requires:
* Molecular oxygen (O2)
* NADH
* Cytochrome b5
* Dietary linoleic acid is
desaturated at carbon 5 to produce **arachidonyl-CoA**
38
Inactive PDC is
Phosphorylated (by ***PDC kinase)***
39
The effect of glucagon on the short-term regulation of HMG-CoA Reductase
Glucagon ( and AMP-Activated PKK) phosphorylate and activate [AMP-Activated PK\_p] then Phosphorylates the HMG-CoA reductase and makes it inactive [HMG-CoA Reductase\_p]
40
•Deficiency of this complex leads to mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) disorder
•_Deficiency in NADH:Ubiquinone oxidoreductase_ **(complex I)** leads to mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) disorder
41
Allosteric effect of F-2,6-BP on F-1,6-BPase
F-2,6-BP allosterically **inhibits** F-1,6-BPase
42
Pyruvate Dehydrogenas complex
## Footnote
a- Components
b- required coenzymes
c- deficiency of coenzymes
»A multisubunit complex with three enzymatic activities
»Requires **five coenzymes** for its activity:
**_˃Thiamine pyrophosphate, lipoic acid, CoA, FAD and NAD+_**
»Deficiencies in thiamine (B1) or niacin (B3) can cause neurological and cardiovascular disorders due to:
˃An **inability** to generate ATP
˃Accumulation of TCA cycle precursors **(lactic acidosis)**
43
1. The enzymes by which the liver overcomes the irreversible reactions of glycolysis (during gluconeogenesis)
2. Which ones are missing in muscles?
The liver overcomes the irreversible reactions using:
A. **Pyruvate carboxylase (PC) (absent in muscles)**
B. Phosphoenolpyruvate carboxykinase (PEPCK)
C. Fructose-1,6-bisphosphatase (F-1,6-BPase)
D. **G-6-Phosphatase (absent in muscles)**
44
Fate of cytosolic citrate (fa synthesis)
citrate lyase (aka citrate cleavage enzyme) breaks citrate down into:
Acetyl co A and OAA
Later, OAA--\>malate --\> pyruvate
45
The TCA step that forms fumarate
## Footnote
enzyme and its location
»***Succinate dehydrogenase*** converts succinate to fumarate
succinate + E-FAD → fumarate + E-FADH2
**˃embedded in the inner mitochondrial membrane** as part of **Complex II**
46
Specificity and function of VDACs
Votlg-Dep Anion Channel (outer mt membrane) Nonspecific and allow different molecule to cross membrane: Phosphate, chloride, pyruvate, citrate, ADP and ATP Several kinases such as hexokinase bind to cytosolic part of these channels to have access to newly synthesized ATP
47
The enzymes required for fatty acid synthesis
Acetyl-CoA carboxylase
Fatty acid synthase (FAS)
48
the effect of increase in I/g ratio on acetyl Co-A synthesis
1. dephosphorylation of PDC (insulin **activates *PDC phosphatase)***
2. increased in synthesis of:
1. malic
2. G6Pdehydrogenase
3. citrate lyase
3. citrate accumulation --\> inhibited isocitrate dehydrogenase --\> citrate leaving mitochondria
All caused by and increase in insuling
49
4 general parameters for TCA regulation
1. ***citrate ynthase*** (depends on the reactants and products)
2. liver NADH/NAD+ ratio impact on acetyl-coA
3. NADH/NAD+ ration effect on ***dehydrogenases***
4. Ca2+ enhances the the production of **NADH (first 2)**
50
results in decreased levels of glucose in CSF (cerebrospinal fluid), which leads to intractable seizures in infancy and developmental delay
GLUT-1 deficiency syndrome hereditary disease affecting the NS.
51
% of dietary cholesterol absorbed from diet
50%
52
Complex II: components and function ETC-OXPhos
Succinate dehydrogenase electrons from the succinate dehydrogenase– catalyzed oxidation of succinate to fumarate move from the coenzyme, FADH2 to an Fe-S protein
53
The short term regulation of glucagon and insulin on HMG-CoA reductase activity
Insulin functions via phosphatase- forms the active form [HMG-CoA Reductase\_X] Glucagon and active AMP-Acivated Protein Kinase-P(PK-P)- Promote the inactive form [HMG-CoA Reductase\_p]
54
dephosphorylated HMG-CoA reductase is
active
55
•Phosphoglucose isomerase (GPI)
Phosphoglucose isomerase deficiency
Conversion of G6P to F6P
•The isomerisation of G-6-P into F-6-P is catalyzed by Phosphoglucose isomerase (GPI)
Phosphoglucose isomerase deficiency leads to hydrops fetalis, a severe form of the deficiency. Most severe cases do not survive to birth.
56
fa synthesis summary
* FAs synthesis is catalyzed by acetyl-CoA carboxylase and fatty acid synthase
* Both enzymes are tightly regulated
* FAs are the components of complex lipids
* Essential FAs must be provided by diet
* Some of the essential FAs can be transformed by elongation and desaturation to allow for the synthesis of other molecules such as:
* Prostaglandins and other eicosanoids
57
the products form during NADH oxidization by malate dehydrogenase (cytosolic isoenzyme)
malate dehydrogenase is a shuttle for NADH (sine innter mitochondrial membrane dosnt have a transporter for NADH). Oxaloacetate reduction to malate
58
NADH shuttles of mitochondria (Cytosol--\> matrix)
glycerophosphate shuttle glycerophosphate dehydrogenase malate-aspartate shuttle malate dehydrogenase
59
chylomicrons
transport of biliary and dietary cholesterol from intestine
60
Hexokinase a- reaction b- inhibition c- function
a- catalyzes the phosphorylation of Glucose. G6P is the finial product. b- Inhibited by G6P c- traps the glucose inside the cell
61
The irreversible rxns of glycolysis:
Phosphorylation rxns e.g. G --\> G6P F6P --\> F1,6-bisP
62
What gets transported into the matrix via malate-asp shuttle:
malate moves into the matrix
63
These diseases are caused by:
1. **Defeciency** in *NADH:Ubiquinone oxidoreductase*
2. **point mutation** (mtDNA) for genes that code for:
* *NADH:Ubiquinone oxidoreductase* OR
* *NAHD dehydrogenase*
1- MELAS
2- LHON
64
reaction catalyzed by cytosolic malate dehydrogenase
OAA to malate while using NADH
65
Biotinidase deficiency
Biotinidase deficiency, an autosomal recessive trait, is a disorder in which the body is unable to reuse and recycle biotin. It is classified as a **multiple carboxylase eficiency**.
Signs and symptoms appear within the first months of life but the age of onset varies. Profound deficiency leads to seizures, weak muscle tone (hypotonia) breathing problems and delayed development. If not **treated with biotin supplement,** the disorder leads to hearing loss, vision loss, hair loss (alopecia), ataxia, skin rashes, and candidiasis.
66
The effects of F1P on fructokinase
inhibition
but prior to inhibiton of fructokinase, F1P causes ATP overuse (aka AMP overload)
As AMP conc. inc., more AMP will be degraded, if excessive --\> uric acid formation
67
Justify hypoglycemia in fructose intolerance
Reactions catalyzed by aldolase:
1- eavage of fructose 1,6-bisphosphate (**central reaction to glycolysis**), and
2- condensation gyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-bisphosphate
**•F1,6 BP is essential for gluconeogenesis**
**•Absence of F1,6 BP** leads to **low glucose** de novo synthesis
•Justifies hypoglycemia in fructose intolerant patients
68
The action of GSIS is mediated by this molecule found on B- cells of the pancreas:
Glucokinase (generally found in liver and pancreas) in B-cells it functions as glucose sensor to regulate GSIS (Glucose Stimulated Insulin Secretion).
69
GLUT-1
Glucose transporter of the brain ( Glial cells express this transporter) and erythrocytes (RBCs)
70
Rate limitting Step of TCA
The oxidation and decarboxylation of isocitrate catalyzed by ***isocitrate dehydrogenase***
71
The Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive human malformation syndrome resulting from an inborn error of cholesterol synthesis.
3β-hydroxysterol ∆7-reductase
72
What gets transported into the matrix via glycerophosphate shuttle
Glycerol-3-phosphate
73
insulin-dependent glucose transporter of adipose and muscle tissues
GLUT-4
74
Hexokinase vs Glucokinase 1- location 2- Vmax
Hexokinase is found in most tissues ( low Vmax and low Km) But Glucokinase is unique to liver and pancreas (high Vmax and Km)
75
Regulation of Gluconeogenesis through the regulation of **Fructose 1,6 bisphosphatase**
nInsulin and glucagon regulate gluconeogenesis
nF-1,6-BPase is allosterically regulated
nF-2,6-BP allosterically inhibits F-1,6-BPase
76
Regulation of gluconeogenesis in liver and muscle
High levels of glucagon activate lipolysis
In the liver, the increase [acetyl CoA]:
Stimulates gluconeogenesis
Inhibits PDH
Allosterically activates pyruvate carboxylase
In the muscle, glucose utilization is limited by:
Low GLUT-4, &inhibition of PDH by high [acetyl CoA]
Lipolysis in muscle Leads to:
increased [acetyl CoA], which causes
§the inhibition of PDHC, leading to
§the conversion of pyruvate to lactate → liver via Cori cycle for use in gluconeogenesis
77
Aldolase Deficiency and Fructose intolerance
It catalyzes the cleavage fructose-1 phosphate into D-glyceraldehyde and dihydroxytacetone phosphate
•D-glyceraldehyde is then phosphorylated into glyceraldehyde-3-phosphate (GAP)
**•GAP is an intermediate in glycolysis and gluconeogenesis**
* If F1P is **not cleaved** → accumulation → inhibition of fructokinase → accumulation of fructose in the blood.
* Before inhibition of fructokinase, formation of F1P → ATP overuse and accumulation of AMP
* Degradation of AMP → uric acid formation
* If lactate is high → reabsorption of uric → uricemia
78
Compounds that regulate the HMG-CoA reductase in short-term by promoting proteolytic cleavage of the enzyme
@ H. conc. Cholesterol @ H. conc. bile The bind to HMG-CoA reductase and make it more susceptible to proteolytic cleavage
79
The mt. location in which the electron and H+ electrolchemical has its highest conc.
across the inner mitochondrial membrane
80
The role of acetyl-CoA and NADH on PDC regulation
Acetyl-CoA and NADH (products of PDC) activate ***PDC kinase* ([PDC-P] is inactive).**
Activated PDC kinase causes inhibition of PDC
Acetyl-Coa and NADH are also **negative allosteric** regulators of PDC
81
Regulation of pyruvate kinase (liver)
activated by F1,6-BP
inhibited by phosphorylation (glucagon, epinephrine, PKA and inc. cAMP)
Inhibited bu ATP, Alanine
82
Phosphorylated PK (pyruvate kinase) and PDC are
inactive
83
The molecule that accepts electron from NADH dehydrogenase and succinate dehydrogenase
Coenzyme Q
84
Phosphorylated HMG-CoA reductase is
inactive
85
Regulation of acetyl Co-A synthesis
* Cytosolic acetyl-CoA generation is stimulated by the increase in insulin/glucagon ratio
* Insulin activates pyruvate dehydrogenase
* Pyruvate dehydrogenase is activated by dephosphorylation
* Insulin activates the PDC phosphatase
* Insulin also induces the synthesis of:
* Malic enzyme
* Glucose-6-phosphate dehydrogenase, and
* Citrate lyase
* The accumulation of citrate is due to the inhibition of isocitrate dehydrogenase
* This accumulation leads to citrate leaving the mitochondria
86
Factor determining the fate of pytuvate in acetyl-coA production
pyruvate can get converted to acetyl coA by pyruvate dehydrogenase.
Pyruvate also can get converted to OAA by pyruvate carboxylase.
**When Acetyl Co-A is high --\> pyruvate carboxylase is activated**
87
The component of ETC without an proton pump
Complex II- succinate dehydrogenase (since it dosnt span the membrane
88
The main form of glucose storage mainly found in liver and muscle
Glycogen
89
Glucogenic a.a. used in gluconeogenesis
The enzymes
1. Alanine
1. ***Alanine aminotransferase (ALT)***
2. Ala --\> pyruvate
2. Aspartate
1. ***Aspartate aminotrasferase (AST)***
2. Asp ---\>OAA--\>PEP
1. OAA--\>PEP catalyzed by ***PEPcaroboxykinase***
2. Asp+malate --\> oxaloacetate (malate shuttle)
3. Glutamate
1. ***Glutamate dehydrogenase (DLDH)***
2. Glu --\> a-ketoglutrrate (a-ketoglutrate --\> OAA --\> PEP
90
Rate limitting enzyme (rxn) of FA synthesis
## Footnote
reaction
required coenzymes
•Cytosolic Acetyl-CoA is converted to malonyl-CoA by an addition of a carboxyl group
**•Biotin and ATP are required for this reaction**
***•\*Acetyl CoA carboxylase*** is the rate-limiting enzyme of FA synthesis
91
List the components of ETC
I- FMN, FAD-containing dehydrogenases CoQ Cytochrome bc1 Cytochrome c Cytochrome oxidase a+a3
92
MODY type 2 cause: manifestation: treatment:
mutation in the pancreatic glucokinase gene (autosomal dominant disorder) manifest as nonprogressive hyperglycemia can be managed by diet alone
93
1st step of cholesterol biosynthesis
begins with two condensation reactions 3-acetyl-CoA --\> HMG-CoA
94
The coenzymes of a***-ketoglutrate dehydrogenase*** and the impact of **chronic alcohol consumption**
Coenzymes: thiamine pyrophosphate, lipoic acid, FAD, NAD+, and CoA\*
chronic consumption of alcohol leads to **vitamin B1/thiamine, deficiency** that is normally converted to thiamine pyrophosphate for use as a coenzyme. Symptoms of this deficiency are neurological due to insufficient energy generation within the nervous system.
95
Rate limitting, irriversible reaction and comitted step of glycolysis
Conversion of F6P to F-1,6- BP
•The phosphorylation of F6P is catalyzed by phosphofructokinase-1 (PFK-1) yielding F-1,6-BP (rate limiting and irreversible reaction; committed step)
Phosphofructokinase deficiency causes an inefficient use of glucose stores by RBCs and muscle leading to hemolytic anemia and muscle cramping.
96
The function of medications that inhibit HMG-CoA reductase
statins- cholesterol lowering drugs
97
The role of EPINEPHRINE in uncoupling of ETC and thermogenesis
act hormone-sensitive lipase --\> relase of FAs free FA activation of thermogenin CoQ reduction of ATP synthesis
98
Low [ADP] and ETC functioning
inhibits the ETC when ADP is low
99
Regulation of Acetyl Co-A carboxylase
* Acetyl CoA carboxylase is regulated by:
* 1. Phosphorylation
* Inhibited by AMP-activated protein kinase
* Activated by dephosphorylation
* 2. Allosteric modification:
* Activated by citrate
* Inhibited by palmitoyl-CoA
* 3. Induction of its synthesis
* High insulin/glucagon ratio induces its synthesis
100
The enzyme and the rxn of the glycolysis that yields the first ATP
Formation of ATP through Substrate-level phosphorylation
* A ***Phosphoglycerate kinase*** catalyzed reaction yields:
* The first ATP, and
* 3-phosphoglycerate (substrate for 2,3-Bisphosphoglycerate synthesis)
101
respiratory control of energy production
Low ADP or P --\> low ATP
Low ADP --\> blocks NADH and FADH2 oxidation
Accumulation of NADH and FADH2 --\> depletion of the oxidized form
102
Name an inhibiter of complex V of ETC
What is the end result of ETC inhibition
Oligomycin bind to **ATP-synthase (complex V)** and blocks H+ channels
ETC and phosphorylation are tightly coupled, inhibition PHOS inhibits OX as well.
103
3 biologically active compounds that utilize cholesterol as a precursor
bile acids/salts steroid hormones (pregnenolone) vit. D
104
Two inhibitors of substrate level phosphorylation
Floride and arsenate
105
The effects of Oligomycin on ETC, as well asthe blood and urine lactate levels.
Oligomycin ***_inhibits_*** ATP-synthase and blocks H+ channel
Results in _high levels_ of accumulation of _lactate_ in **blood** and **urine**
106
Decreased [F-2,6-BP] causes:
qInhibition of glycolysis
qActivation of gluconeogenesis, and
qActivation of lipolysis
107
Reduction of a β-ketoacyl group on the fatty acid synthase complex .
NADPH is the reducing agent
* The ketone group is reduced to an alcohol
* Dehydration occurs by removing water
* The double bond is reduced
* NADPH provides the reducing power
108
The big pics of the usage of glucogenic aa. in gluconeogenesis
To make either PYR,OAA
Pyruvate made from alanine ***(ALT)***
OAA made directly from aspartate ***(AST)***
OAA made indirectly from glutamate (***GLDH*** makes a-ketoglutrate and aketoglutarate is converted to OAA)
109
Location and the purpose of hydroxyl group in cholesterol
C3 of the ring required for esterification (compared to sterol, cholesterol has OH and a side chain at C17 and a double bond C5 and C6
110
Induce of **expression** of various **cytochrome mono-oxidase**
Drug and alcohol
Drug and alcohol abusers **prone** to deleterious effects of ROS formed by **P-450s**
111
Regulation of the enzyme that catalyzes the _aldol condensation step of TCA_
»First step of TCA is the formation of citrate
oxaloacetate (OAA) + acetyl CoA + H2O → citrate + HS-CoA + H+
˃citrate synthase catalyzes aldol condensation
***»Citrate synthase*** is inhibited by
˃Citrate (product inhibitor)
˃NADH
˃Succinyl CoA
»Regulation is determined by availability of substrates
112
Patient with this mt. disorder develop l_oss of **central vision** in their 20s to30s._
Leber's hereditary optic neuropathy
## Footnote
Complx I disorder- caused by point mutation (mtDNA) for genes that code for:
NADH:Ubiquinone oxidoreductase OR
NAHD dehydrogenase
113
The sources of acetyl CoA for the biosynthesis of cholesterol are:
B-oxidation of fatty acids Dehydrogenation of pyruvate Oxidation of Ketogenic amino acids.
114
The corticosteroids made from pregnenolone are:
glucocorticoids and mineralocorticoids Both are referred to as corticosteroids
115
thermogenin
UCP of the brown adipose tissue associated with heat production Non-shivering thermogenesis
116
function and location of HMG-CoA reductase
ER membrane bound enzyme required for the committed step of cholesterol biosynthesis
117
The effects of(liver) the increase [acetyl CoA]:
(gluconeogenesis)
Stimulates gluconeogenesis
**Inhibits PDH**
Allosterically **activates pyruvate carboxylase**
118
Aldolase deficiency and fructose intolerance
Rxns catalyzed by alsolase B
1. cleavage fructose-1 phosphate into D-glyceraldehyde and dihydroxytacetone phosphate
2. cleavage of fructose 1,6-bisphosphate (central reaction to glycolysis),
3. **condensation** of glyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-bisphosphate
119
»When energy levels in the cell are high
˃ATP depresses TCA cycle activity and leads to accumulation of citrate and its efflux to cytosol
»Cytosolic citrate stimulates
˃FA synthesis (Acetyl-CoA carboxylase)
»Cytosolic citrate inhibits
˃Glycolysis phosphofructokinase-1(PFK-1)
120
The major source of C for TCA
Glycolysis
121
**Kearn-Sayre syndrome**
caused by pt mutation of mt.DNA that impacts **complex II**
Patients with this syndrome present with _short stature_, _complete external ophthalmoplegia_, _pigmentary retinopathy_, _ataxia_ and _cardiac conduction defects_
122
reaction catalyzed by HMG-CoA reductase
HMG CoA + 2NADPH --\> Mevalonate + 2NADP+
123
Neuron-specific glucose transporter of the brain
GLUT-3 (NSGT)
124
The ETC component capable of interacting with oxygen
cytochrome a+a3 (cytochrome oxidase)
125
Three glycolytic enzymes that their transcription is controlled via Insulin/glucagon
1. Glucokinase
2. PFK-1
3. Pyruvate kinase
126
The reaction catalyzed by isocitrate dehydrogenase
»The oxidation and decarboxylation of isocitrate is catalyzed by ***isocitrate dehydrogenase*** (rate limiting step)
**isocitrate + NAD+ → a-ketoglutarate + NADH + H+ + CO2**
˃Allosterically
+activated by ADP and Ca2+
+inhibited by ATP and NADH
127
Isocitrate formation
Inhibition of the rxn
»Citrate → isocitrate catalyzed by ***aconitase***
˃Can be inhibited by **fluorocitrate** produced by ***citrate synthase*** from fluoroacetate (used as rodenticide and for wild life control)
+fluoroacetate is a **potent toxin**
+**2-fluorocitrate** → inhibits ***aconitase*** activity→ inhibits TCA cycle → death
128
Regulation of the rate of oxygen consumption (ETC)
[ADP] HIGH: oxygen consumption is high, more NADHs are reduced and NAD+ returned to TCA. More H2O made
129
Complex I: components and function ETC
NADH dehydrogenase (formation of NADH ) has Flavin Mono Nucleotide (FMN) At this complex electrons move from NADH to FMN to the Fe and Iron-Sulfur center and then CoQ
130
Clinical Correlates summary of glycolysis and ATP generation
ØRed blood cells (RBCs) rely completely on glycolysis as a source of energy. Deficiencies of glycolytic enzymes will effect RBC function leading to hemolysis
ØHereditary deficiency of GLUT-1 results in decreased glucose in the cerebrospinal fluid, which leads to intractable seizures in infancy and developmental delay
ØDeficiency in the A isoform of aldolase (muscle and RBCs) leads to a nonspherocytic hemolytic anemia with episodes of rhabdomyolysis followed by a febrile illness
ØDeficiency of triose phosphate isomerase (TPI) leads to neonatal-onset hemolytic anemia, progressive hypotonia leading to eventual diaphragm paralysis and cardiomyopathy
ØEnolase is inhibited by fluoride. If patient’s blood sample for glucose quantification is collected in tubes containing fluoride
ØHbF has a lower affinity for BPG than does HbA, which leads to higher affinity for O2
ØMaturity-onset diabetes of the young (MODY) type 2, an autosomal dominant disorder, is caused by a mutation in the glucokinase gene leading to nonprogressive hyperglycemia, which can be managed by diet alone.
ØPhosphofructokinase deficiency causes an inefficient use of glucose stores by RBCs and muscle leading to hemolytic anemia and muscle cramping
ØDeficiency in pyruvate kinase causes a decrease in ATP production from glycolysis by RBCs leading to hemolytic anemia
131
Regulation of TCA cycle
»Citrate synthase is
## Footnote
˃Regulated by availability of the substrate – oxaloacetate
˃Inhibited by its product, citrate and succinyl-CoA
»In the **liver,** NADH/ NAD+ ratio determines the fate of **acetyl-CoA**
˃**High ratio** – acetyl-CoA goes into **ketone body** synthesis
˃**Low ratio** – acetyl-CoA enters **TCA cycle**
»TCA cycle responds rapidly to
˃Changes in ATP/ADP and NADH/ NAD+ ratios
˃Increased ATP demand
»NADH/ NAD+ ratio regulates the activity of TCA ***dehydrogenases***
**˃High** ratio leads to **inhibition**
**˃Low ratio** leads to **activation**
»Ca2+ activates the production of the first two NADH
132
In form of lipoprotein from extrahepatic tissues
HDL
133
Between hexokinase and glucokinase, which one has higher affinity to glucose:
hexokinase (thus it is reasonable that it is active in fasting state).
134
Determine the targets of the following respiratory poisons:
1- Antimycin A
2- CO and CN-
1- Antimycin A (fungacide) inhibits **Complex III**
2- CO and CN- inhibits **Complex IV**
135
activates glucokinase
glucokinase is activated by its substrate
136
Palmitate Synthesis
Palmitate synthesis on the fatty acid synthase
Palmitoyl-CoA can be further elongated and desaturated to produce other fatty acids
137
Anaplerotic reactions of TCA
general overview
low OAA --\> inc. accumulation of acetyl-CoA --\> activation of pytuvate carboxylase --\> increased synthesis of OAA
138
The effect of high acetyl coa on yruvate carboxylase
activation
(pyruvate carboxylase makes OAA from PYR in liver)
139
GLUT-4 can be found in:
GLUT-4 is insulin-dependent glucose transporter of: 1- adipose tissue 2- muscle cells
140
PFK2 activation in muscle and liver
* In the liver, PFK-2 is:
* activated by ↑[F6P] (the substrate), and
* **Inhibited** by **PKA** during **fasting** conditions
* **Protein kinase A** is activated by cAMP, the synthesis of which is induced by the binding of glucagon
* In the muscle, PFK-2 is:
* •**Activated by↑[AMP]** and **↑[norepinephrine]** resulting in **increased [F2,6-bisP]** → **activation of glycolysis** → ATP synthesis for muscle contraction
141
reation catalyzed bu malic enzyme
malate to pyruvate and making NADPH and CO2
142
transporters of the inner mitochondrial membrane
Adenine Nucleotide Translocase (ANT) Phosphate transporters
143
The effect of low cholesterol on transcription of HMG-CoA reductase
SCAP-SREBP remains intact, thus no gene activation
144
Fate of cytosolic OAA during fa synthesis
* OAA resulting from the cleavage of citrate is reduced to **malate** by cytosolic ***malate dehydrogenase (NAD+-dependent)*** in presence of NADH
* Malate is then converted to pyruvate
* In this reaction NADPH is produced and CO2 is released
* The decarboxylation reaction is catalyzed by malic enzyme or NADP+-dependent malate dehydrogenase
* NADPH will be used for reduction on the fatty acid synthase complex
145
Determine the targets of the followoing respiratory poisons:
Amytal and Rotenone
Complex I of ETC
146
The tissue most affected by arsenic poisioning
brain
Arsenic intereferes with glycolysis and TCA
147
Acetyl-CoA carboxylase
* Catalyzes the synthesis of malonyl-CoA
* Malonyl-CoA is the immediate donor of the two-carbon units
148
The lipoprotein(s) that don't contribute to fasting plasma cholestrol
chylomicron- only found after a meal
149
5 general pathways in which glucose is utilized:
Glycolysis Glycogen synthesis UDP-Glucose Pentose-Phosphate Pathway Sorbitol
150
Sources of lactate
Lactate as a substrate (liver) of gluconeogenesis
1. RBC
2. Skeletal muscle
3. skin
4. lens and cornea
Lactate is the end product of glycolysis in the absence of oxygen:
RBCs
Intensely exercising muscle
151
The disease that's caused by pt mutation of mt.DNA that impacts complex II. Patients with this syndrome present with short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia and cardiac conduction defects
Kearn-Sayre syndrome
152
The impact of F2,6-bP reduction on glycolysis, gluconeogenesis, and lipolysis
reduction of F2,6-bp red. Glycolysis inc. gluconeogenesis inc. lipolysis
153
Glucose enters brain via
GLUT-1 and GLUT-3
154
Biosynthesis of mevalonate
Begins with HMG Co-A as the reactant second step of cholesterol biosynthesis, which is also the committed step and catalyzed by HMG-CoA reductase
155
Aldolase B deficiency
•Deficiency of Aldolase B leads to pyruvate accumulation → lactate accumulation → lactic acidemia
156
The enzymes responsible for the synthesis of:
1. 2-Phosphoglycerate
2. PEP
Synthesis of 2-phosphoglycerate
•***Phosphoglycerate mutase*** moves phosphate to C-2 leading to the formation of 2-phosphoglycerate
Synthesis of phosphoenolpyruvate (PEP)
* ***Enolase*** catalyzes a reaction leading to the formation of:
* PEP, and
* H2O
157
The function of VDAC as a transporter in mt
diffusion of synthesized ATP out of the mt into the cytosol Voltage dependent anion channel
158
Gluconeogenesis from Lactate
Lactate is the end product of glycolysis in the absence of oxygen:
* RBCs
* Intensely exercising muscle
The **muscle** lacks G-6-Pase and pyruvate carboxylase (PC) → **cannot perform gluconeogenesis**
Lactate from exercising muscle and RBCs → blood → liver → pyruvate → glucose (via gluconeogenesis) → blood → brain and RBCs (Known as Cori Cycle)
The reaction catalyzed by ***LDH*** is irreversible **(lactate \<--\> pyruvate)**
159
Aldolase A deficiency and the rxn catalyzed by it
4. Cleavage of F-1,6-BP
* Aldolase catalyzes the cleavage of F-1,6-BP into:
* Dihydroxytacetone phosphate (DHAP), and
* Glyceraldehyde 3-phosphate (GAP)
* Deficiency in aldolase A (**muscle and RBCs**) leads to a **nonspherocytic hemolytic anemi**a with episodes of rhabdomyolysis (breakdown of muscle tissue) followed by febrile illness **(kidney damage)**
160
list the cargos of adenine nucleotide antiporter in mitochondria Also list the direction of transport
1 ATP from matrix to cytosol 1 ADP from cytosol to matrix
161
Sources of Acetyl CoA
Ethanol
Pyruvate (from glycolysis and aa, spc alanine)
The sugar (Glucose) (which makes pyruvate)
The ketone body-acetoacetate
The fatty acid- Palmitate
162
liver F-1,6BPase deficiency
Deficiency of the liver F-1,6BPase leads to neonatal hypoglycemia, acidosis,irritability, tachycardia, dyspnea, hypotonia, and moderate hepatomegaly
163
Cofactor for biotin carboxylase
biotin
164
The enzyme that catalyzes the substrate level phosphorylation of TCA
»*Succinate thiokinase* catalyzes substrate-level phosphorylation
Succinyl CoA + Pi + GDP → succinate + GTP + CoA
»GTP and ATP are interconvertible:
GTP + ADP ↔ GDP + ATP
˃This conversion is catalyzed by ***nucleoside diphosphate kinase***
165
The events leading to the formation of an electrical and a PH gradient across the inner mitochondrial membrane
NADH and FADH2 donate electrons to ETC Leads to e- flow coupled with H+ transport
166
The enzyme responsible for the conversion of DHAP to GAP and its deficiency
5. Isomerisation of DHAP into GAP
* Triose-P isomerase converts DHAP into GAP
* Deficiency of triose phosphate isomerase (TPI) leads to **neonatal-onset hemolytic anemia**, **progressive hypotonia** leading to eventual diaphragm paralysis and **cardiomyopathy**
167
Sources of NADPH for fa synth
168
Hormonal effect on an allosteric Effector in the Regulation of Gluconeogenesis
1. Insulin and Glucagon
2. concentration of F-2,6-BP
In the **presence of glucagon,** *F-2,6-BPase* catalyzes
F-2,6-BP → F-6-P ( enters gluconeogenesis).
In the presence of insulin, **PFK-2** catalyzes
F-6-P → F-2,6-BP
In short:
glucagon lowers F26BP, promote gluconeogenesis
Insulin increase F26BP, inhibits gluconeogenesis
169
Components of the complex that regulates transcription of HMG-CoA reductase gene
SREBP (binds to SRE) SCAP-SREP cleavage activating protein
170
The reaction catalyzed by a-ketoglutarate dehydrogenase
»The oxidative decarboxylation of a-ketoglutarate is catalyzed by ***a-ketoglutarate dehydrogenase*** complex
a-ketoglutarate + NAD+ + CoA è succinyl CoA + CO2 + NADH
˃Releases CO2 and produces the **second NADH**
˃Coenzymes: thiamine pyrophosphate, lipoic acid, FAD, NAD+, and CoA\*
˃Inhibited by
+NADH and succinyl CoA (feedback inhibition) and
+ATP and GTP
˃Activated by
+Ca2+
171
Formation of Gluconeogenic Intermediates From Carbon Sources
(main substrates for de novo synthesis in liver)
nTo synthesize glucose de novo, the liver uses as main substrates:
* **Glucogenic amino acids (from the muscle)**
* **Lactate (product of anaerobic glycolysis )**
* **Glycerol (Triglyceride catabolism/lipolysis)**
nGlycogen in the muscle is NOT used to maintain blood glucose
172
Purpose of Cori Cylce
Allows gluconeogenesis from lactate.
Since muscles lack PC and G6Pase, the lactate produced enters the circulation and enters the liver.
In the liver, it gets converted to pyruvate (LDH), and to glucose (via gluconeogenesis)
173
Pyruvate Dehydrogenase deficiencies
## Footnote
Causes and Symptoms
Mode of inheritance
Severity
»Pyruvate dehydrogenase deficiency is the **major cause of congenital lactic acidemia.**
»Symptoms are similar to pyruvate carboxylase deficiency
˃Leigh disease
»The most common PDC genetic defects are in genes coding for **alpha unit of E1**
˃The E1 alpha gene is X-linked but affects both males and females
+Categorized as **X-linked dominant disorder**
»The severe form of PDC deficiency presents with excessive lactic acidosis at birth
˃Accumulated pyruvate leads to lactic acid synthesis via ***LD***
˃Results in n**eurological symptoms** because the **_brain_**:
+relies on glucose as a main source for Acetyl CoA for energy and
+is highly sensitive to acidosis
174
chylomicron remnants
In peripheral tissue chylomicrons are converted to chylomicron remnants
175
Pyruvate Dehydrogenase
As a major source of acetyl-CoA
»A bridge between glycolysis and TCA cycle
˃Is not part of TCA cycle
»Converts pyruvate to acetyl-CoA
˃Key **irreversible** step
˃A **major source** of acetyl CoA
»Important site for regulation
176
PDC
## Footnote
a- inhibition
b- activation
c- allosteric regulation
»PDC is inhibited by phosphorylation catalyzed by PDC kinase which is
˃***PDC kinase*** activated by:
+ATP (high energy signal)
+Acetyl-CoA and NADH (Products of PDC)
˃***PDC kinase*** inhibited by:
+ADP (low energy signal)
+Pyruvate (Substrate of PDC)
»PDC is **activated by dephosphorylation** catalyzed by ***PDC phosphatase*** which is
˃***PDC phosphatase*** activated by:
+Calcium (Ca+)
»Allosteric Regulation of PDC:
˃Acetyl-CoA and NADH are negative allosteric effectors
˃CoASH and NAD+ are positive allosteric effectors
177
The effect of insulin in ***citrate lyase***
induction
Citrate lyase breaks down citrate into OAA and acetyl CoA
178
Efflux of TCA intermediates
»High carbohydrate meal generates
˃Citrate efflux into cytosol for fatty acid synthesis
»During fasting malate is transported to cytosol and used in gluconeogenesis
»TCA provides carbon skeletons for **amino acid synthesis**
»In the brain, a-ketoglutarate is converted to neurotransmitters **GABA and glutamate**
»In the liver and bone marrow , succinyl CoA can be used to form **heme\***
179
activation of transcription of HMG-CoA reductase gene is initiated by
SREBP binds to SRE (sterol regulatory complex.
180
failure in the function of G6Pase
## Footnote
**GSDI**
failure in the function of glucose 6Pase results in **accumulation of G6P** leading to **hepatomegaly, severe hypoglycemia c**ausing lethargy, seizures, brain damage, increased bleeding, and growth retardation (**GSD I** name?)
181
Glucose enters hepatic cells via
GLUT-2
182
the state in which the following enzymes are active in (fed vs fasting state) a- Hexokinase b- glucokinase
a- hexokinase is active in fasting state- It has low km and vmax, ang higher affinity to glucose- also found in most tissues) b- glucokinase is active in fed state.
183
Tissues that express GLUT 2
liver Kidney B cells (Pancreatic cells)
184
The starting point for the biosynthesis of cholesterol
acetyl Co-A
185
Citrate effects on fatty acid synthesis and glycolysis
Citrate
Is the **source of acetyl** carbon for **fatty acid synthesis**
_Inhibits_ ***phosphofructokinase*** – glycolysis
_Activates_ ***acetyl CoA carboxylase*** – fatty acid synthesis
186
Glucokinase vs. Hexokinase (Km comparison)
Hexokinase has LOW km Glucokinase has HIGH Km Hexokinase, phosphorylates glucose to forms G6P.
187
Products of PDC
Acetyl Co-A and NADH
188
Regulatory subunits of PDC
PDC kinase (ihibitor) and PDC phosphatase(activator)
are regulatory subunit within PDC
189
The Cause of **ME-LA-S disorders**
**ME** mitochondria encephalopathy
**LA** lactic acidosis
**S** stroke
Deficiency in complex I
## Footnote
***NADH:Ubiquinone oxidoreductase***
190
GLUT-5 can be found in
small intestine and testes (Glut-5 is fructose specific)
191
Conversion of glucose to cytosolic acetyl-CoA
* In the cytoplasm and through glycolysis, glucose is converted to pyruvate
* Pyruvate then enters the mitochondria to form:
* acetyl coenzyme A (acetyl-CoA) (pyruvate dehydrogenase ) and
* Oxaloacetate (pyruvate carboxylase)
* Acetyl-CoA and OAA condense to form citrate
* Citrate is transported to the cytosol (when in excess)
* In the cytosol, citrate is cleaved into acetyl-CoA and OAA by citrate lyase
* The action of citrate lyase requires ATP
* Citrate lyase is induced by insulin
* The fate of pyruvate is dictated by the levels of acetyl-CoA in the mitochondria
* When [acetyl-CoA] is high:
* Pyruvate carboxylase is activated
192
synthesized ATP utilizes the transporter to translocate from the matrix into the inner membrane space
ANT adenine nucleotide translocase
193
Mechanisms of arsenic poisioning
## Footnote
affected pathways
effects of arsenate and arsenite
the over effect on total [ATP]
the most affected organ
»Arsenic interferes with **glycolysis** and **TCA cycle**
˃**Arsenate** acts as phosphate analog and _inhibits_ **substrate-level phosphorylation** reactions
˃**Arsenite** inhibits enzymes using **lipoic acid** as a cofactor
˃**Both** lead to _decreased production of ATP -_**-\> Low [ATP]**
»Affects the brain, causing neurological problems and eventually death
194
The mutation of this gene cause MODY-type II MODY-maturity Onset Diabetes of the Young
mutation in pancreatic glucokinase
195
Mechanism of action of bile salt sequestrant
A bile acid sequestrant will lower cholesterol by binding to bile acid and disrupting the circulation back into the liver. It will cause more bile acid to be excreted, and thus increasing the use of cholesterol through bile acid synthesis.
196
Transporter with specificity for fructose transport
GLUT-5
197
In addition to the high ADP, in cardiac mitochondrial, --------- activates the TCA, provides an additional push to ETC by increasing NADH production.
Ca
198
Two possible ways to generate NAD+ from NADH
1. In presence of oxygen:
* Pyruvate is degraded to CO2 and H2O, and NADH
* The reducing power of **NADH enters the electron transport chain to generate ATP**
Glycerol 3P and malate-aspartate shuttles
2. In absence of oxygen:
* ***Lactate dehydrogenase*** (LDH/LD) reduces pyruvate to lactate
Pyruvate + NADH ↔ Lactate + NAD+
This reaction is **reversible and pH dependent**
199
Major anaplerotic enzyme and its deficiency
Pytuvate carboxylase
## Footnote
˃Is the major anaplerotic enzyme
˃Forms oxaloacetate from pyruvate
˃Is activated by acetyl CoA
˃Its deficiency can lead to lactic acidosis
200
what activates Malate-Asp shuttle
**Active** only when
(NADH/NAD+) cytosolic \> (NADH/NAD+) mitochondria
When more NADH in cytosol
201
The lipoprotein(s) that contribute to fasting plasma cholesterol
LDL, VLDL, HDL
202
glucokinase can be found in these tissues:
liver and pancreas (In the pancreas, it functions as glucose sensor in B-cells, where it controls glucose-stimulated insulin secretion (GSIS).
203
How does the liver circumvent the irreversible reactions of glycolysis
nDuring gluconeogenesis, the liver has to circumvent the irreversible reactions of glycolysis
q1. Hexokinase (reversed by D)
q2. PFK-1 (reversed by C)
q3. Pyruvate kinase (reversed by A and B)
nThe liver overcomes the irreversible reactions using:
qA. Pyruvate carboxylase (PC)
qB. Phosphoenolpyruvate carboxykinase (PEPCK)
qC. Fructose-1,6-bisphosphatase (F-1,6-BPase)
qD. G-6-Phosphatase
204
Short-Term Regulation of HMG-CoA reductase
Phos/ Dephos
Inhibited by phosphorylation
Low ATP (through AMP-activated protein kinase) and Glucagon promote phosphorylation
Activated by dephosphorylation
Insulin activates phosphatase
205
Transcriptional Regulation of HMG-CoA reductase
High cholesterol prevents its cleavage:
No activation of HMG-CoA reductase expression.
When cholesterol level is low:
SCAP-SREBP complex translocates from ER to Golgi and is cleaved by S1P and S2P proteases.
Liberated SREBP’s DNA-binding domain translocates to nucleus and activates transcription of many genes including HMG-CoA reductase gene.
206
Synthesizes cholesterol esters
ACAT
Acey-CoA Cholestrol Acyltransferase
207
Smith-Lemli-Opitz Syndrome (SLOS)
•The Smith-Lemli-Opitz Syndrome (SLOS) is the example of a **human malformation syndrome** resulting from an inborn error **of cholesterol synthesis**.
–Autosomal recessive
–Caused by the deficiency of **3β-hydroxysterol ∆7-reductase**
•Infants with severe variant ( type II SLOS) often die from multiple congenital abnormalities.
208
deficiency 3β-hydroxysterol ∆7-reductase
SLOS
209
Cholestrol excretion
Sterol ring **cannot** be degraded by humans.
It is excreted either as **_biliary cholesterol_** or in form of **_bile acids_**.
**Most** of the excreted bile acids are r**eabsorbed** in the gut through an enterohepatic circulation.
210
Components of bile
Bile acid sequestrants function
Bile acid sequestrants are used to lower cholesterol through a **decreased bile acids reabsorption** in the gut.
Bile contains bile acids, cholesterol, lipids, and bilirubin.
211
The rate limitting step of bile acid biosynthesis is catalyzed by:
## Footnote
The function of bule acids
Rate-limiting step is catalyzed by 7a-hydroxylase:
The enzyme is inhibited by the bile acids (end-product inhibition).
They facilitate the absorption of fat-soluble vitamins and drugs.
Prevent precipitation of cholesterol in the gallbladder.
212
Bile Salts
Bile salts are produced by conjugation of bile acids with glycine or taurine.
They have lower pK than bile acids and are better detergents.
They can be converted to secondary bile salts by intestinal bacteria.
Less soluble than primary bile salts.
The reabsorbed secondary bile acids are converted to primary bile acids and bile salts.
213
Progressive Familial Intrahepatic Cholestasis (PFIC)
* They are chronic autosomal recessive disorders causing hepatic fibrosis and end-stage liver disease.
* This group of disorders is caused by the defects in bile secretion and/or absorption cause hepatic and systemic accumulation of bile acids and reduced enteric bile acid availability.
* Clinical symptoms include history of neonatal diarrhea, sepsis and intermittent jaundice.
PFC1- Bile
PFC-2-BA
PFC3-PC
214
Progressive Familial Intrahepatic Cholestasis 1
Byler disease- mutation in ***ATP8B1-*encoding aminophospholipird flippase**
Translocate: PS and PE (from outer inner leaflet)
•The deficiency of ATP8B1 in the hepatocyte results in the loss of asymmetric distribution of phospholipids in the canalicular membrane, decreasing both membrane stability and function of **bile salt export pump (BSEP)** and, as such, causing **bile salt retention in hepatocytes** with consequent defective bile formation; resulting in **cholestasis.**
215
Progressive Familial Intrahepatic Cholestasis 2
•PFIC-2 is caused by mutations in the gene for bile salt **exporter pump (BSEP)** leading to retention of bile salts within hepatocytes.
The **defective canalicular BSEP expression** leads to bile secretory failure and retention of bile salts and other biliary constituents in the hepatocytes leading to progressive **liver damage and cholestasis**
216
Progressive Familial Intrahepatic Cholestasis 3
Free bile acids cause cholangitis
* PFIC-3 is caused by mutations in the gene for **multidrug resistance protein 3 (MDR3) or floppase** resulting in the lack of phosphatidylcholine in bile. **(reduced PC in bile)**
* Free bile acids damage biliary epithelium causing a **cholangitis; inflammation of the bile duct system.**
* Patients usually present in early childhood with cholestasis, jaundice, failure to thrive, and intense pruritus.
217
diseases associated with bile acid metabolism
•Bile salts malabsorption can be caused by:
**–Crohn’s disease**, which is a type bowel inflammatory disease causing decreased bile salts absorption.
–**Celiac disease** is a long term autoimmune disorder primarily affecting the small intestine causing malabsorption.
–**Chronic pancreatitis** is associated with **elevated fecal** bile acids primarily due to their pH induced precipitation.
•High concentration of bile acids in the colon stimulates water secretion and chronic diarrhea.
218
factors that maintain cholestrol solubility
phospholipids and bile salts
If cholestrol to phospholipids and bile salts ratio is more than 1:1 --\> excess cholestrol crystalize
219
Cholestrol Summary
* Component of membranes and precursor of steroid hormones
* Produced by most cells from Acetyl-CoA
* Liver and intestines are the major producers
* HMG-CoA reductase – rate-limiting step
* Short- and long-term regulation
* Primary bile acids are synthesized only in the liver
* 7a-hydroxylase – rate-limiting step
* Functions of bile acids, primary and secondary bile salts.
* Cholesterol balance (enterohepatic circulation)
* Gallstone formation.
