tisdag 1 februari 2011

Kertausta: STEROLIEN biosynteesin otsikoita

Glossary of Biosynthesis of Sterols

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2 sources of cholesterol:
1. Diet
2. De novo synthesis in all cells
4 predominant tissues of Sterol biosynthesis:
1. Liver
2. Adrenal cortex
3. Intestine
4. Reproductive tissues
Main sites where cholesterol functions: (2)
1. Cell membrane component
2. CNS/brain myelinated structures
2 Direct Derivatives of Cholesterol
1. Steroid hormones
2. Bile acids
8 Derivatives of Cholesterol INTERMEDIATES:
-Vitamens D/E/A/K
-Carotenoids
-Rubber
-Plant hormones
-Phytol chain of chlorophyll
-Dolichols
-Ubiquinone/Plastiquinone
-Isoprene
Plant hormones (2):
-Abscisic Acid
-Gibberellic acid
3 Most important derivatives of cholesterol to remember:
-Steroid hormones
-Bile acids
-Vitamin D
In what form is cholesterol in membranes?
Unesterified - FREE
What distinguishes free unesterified cholesterol from esterified?
An -OH instead of Acyl
What enzyme makes free cholesterol esterified?
ACAT - Acyl-CoA Cholesterol Acyl Transferase
What reaction does ACAT catalyze?
Incorporates Fatty AcylCoA into Cholesterol w/ subsequent release of CoASH.
When does ACAT work? Why?
When membranes have too much free cholesterol ACAT esterifies it for intracellular storage or lipoprotein transfer.
What is the function of cholesterol in membranes?
Regulates fluidity and lateral mobility of proteins in the lipid bilayer.
What is the storage form of cholesterol called?
Cholesteryl Ester
What type of molecule is cholesterol?
Amphipathic
Nonpolar = 4 hydrocarbon rings
Polar head = OH
How many carbons are in cholesterol?
27
What allows cholesterol to circulate in the blood?
Apolipoproteins
What is the carbon source for cholesterol synthesis de novo?
Acetyl CoA
3 Sources of AcCoA:
1. FA beta-oxidation (mitochon)
2. Ketogenic amino acid oxidation (leucine/isoleucine)
3. PDH reaction
PDH Cofactors:
-TPP
-Lipoamide
-FAD
Reaction of PDH:
Pyruvate -> AcCoA
What enzyme catalyzes the COMMITTED STEP of Cholesterol biosynthesis?
HMG-CoA Reductase
What are the 4 major stages of cholesterol biosynthesis?
0. Acetate
1. Mevalonate
2. Activated Isoprenes
3. Squalene
4. Cholesterol
What happens in Cholesterol biosynthesis Stage 1? Enzymes?
AcCoA -> Mevalonate
-3 reactions
-Thiolase, HMG-CoA Synthase, HMG-CoA Reductase
What is important re: first 2 reactions in Mevalonate synth?
They are shared with Ketogenesis
What is different about Ketogenesis vs. Mevalonate?
Ketogenesis = mitochondria
Cholest Synth = Cytosol

Hence dif. pools of enzymes
What are the enzymes shared by Ketogenesis & Mevalonate synth?
-Thiolase
-HMG-CoA Synthase
In what tissue are the cytosolic and mitosolic pools found?
Liver Parenchymal cells
Why is Mevalonate synthesis so very important?
Its 3rd reaction is the Commitment step of cholesterol biosynthesis
Where do HMG-CoA reductase and subsequent reactions occur?
Probably in peroxisomes.
What occurs in the 1st reaction of Mevalonate synthesis? Enzyme?
2 AcCoA condensation - releases one CoASH
-Via Thiolase
What is the product of Thiolase?
Acetoacetyl-CoA
What occurs in the 2nd reaction of Mevalonate synth? Enzyme?
Acetoacetyl-CoA is condensed with another AcCoA
-Via HMG-CoA synthase
What is the product of HMG-CoA Synthase?
HMG - b-hydroxy-b-methylgutaryl-CoA
What occurs in the 3rd reaction of Mevalonate synth? Enzyme?
CoASH released from far end of HMG-CoA; C=O reduced to CH2-OH; the protons donated by 2NADPH;
-Via HMG-CoA Reductase
Where is HMG-CoA reductase found, and how is it situated?
-Integral - in the cell membrane
-Active site on cytosolic side
Product of HMG-CoA reductase is:
Mevalonate
What does Mevalonate get converted to? How?
5-Carbon Activated isoprenes by Decarboxylation
How many reactions and enzymes are needed for stage 2 of cholesterol biosynthesis?
4 Reactions/3 enzymes
Enzymes in 5C Activated Isoprene synthesis:
1. Mevalonate 5-phosphotransferase
2. Phosphomevalonate kinase
3. Pyrophosphomevalonate Decarboxylase
Key thing to remember about stage 2 of cholest. biosynth:
IT REQUIRES 3 total ATP
What happens in the 1st reaction of stage 2?
PO4 added to terminal carbon of Mevalonate - replaces the -OH created by HMGCoA reductase.
What happens in the 2nd reaction of stage 2?
Add another PO4 right onto the one added in reaction 1.
What happens in the 3rd reaction of stage 2?
Add another PO4 onto the beta carbon of pyrophosphomevalonate.
What enzymes catalyze reactions 1 and 2?
1. Mevalnt 5-phosphotransferase
2. Phosphomevalonate kinase
What enzyme catalyzes reactions 3 and 4 of stage 2?
Pyrophosphomevalonate decarboxylase - same enzyme for both reactions.
What occurs in reaction 4 of stage 2?
Decarboxylation of carbon 1 and loss of PO4 from carbon 3
What results from decarboxylating 3-Phospho-5-pyrophosphomevalonate?
2 isomers:
-d3-isopentenyl pyrophosphate -Dimethylallyl pyrophosphate
What happens in Stage 3 of cholesterol biosynthesis? (in broad terms)
Condensation of 6 activated 5-C isoprene units to make Squalene
What substrate is used in stage 3?
1 NADPH
So substrates for:
-Stage 1
-Stage 2
-Stage 3
1 = 2 NADPH
2 = 3 ATP
3 = 1 NADPH
How many steps are entailed in Stage 3 of cholesterol synth?
3 steps: C5 -> C10 -> C15 -> C30
What enzymes are used in Stage 3?
-Prenyl transferase (Rxns 1/2)
-Squalene synthase (Rxn 3)
What terms describe the nature of the 3 condensation reactions?
Rxns 1/2 = head-to-tail

Rxn 3 = head-to-head
What are the intermediates in Squalene synthesis? How many Cs?
1. Geranyl PPi (10 C)
2. Farnesyl PPi (15 C)
What is important about Farnesyl PPi?
Used in post-translational protein modification
Where does Farnesylation occur on proteins?
C-terminal Cysteine residue
What is unique about the final condensation of 2 Farnesyl PPi?
-Head-to-Head
-Requires NADPH
What enzyme catalyzes the final step of stage 3?
Squalene synthase
How many carbons are in squalene? How many in cholesterol?
Squalene = 30

Cholesterol = 27
What needs to happen to squalene to make cholesterol?
Cyclization to close rings
In Squalene-Cholest conversion:
-How many reactions?
-How many enzymes?
-What substrates?
-13 reactions
-11 enzymes
-1 NADPH
How does Squalene cyclization get started?
By activating it to Squalene Epoxide
What enzyme makes Squalene 2,3-Epoxide?
Squalene monooxygenase
What does Squalene monooxygenase require?
1 molecule of O2
1 NADPH
What enzyme cyclizes Squalene 2,3-Epoxide?
Oxidosqualene cyclase
What is the product of oxidosqualene cyclase action?
Lanosterol
What needs to happen to Lanosterol to make cholesterol?
(3 things)
-Demethylation of 3 Carbons
-Reduce a double bond
-Migrate another double bond
Substrates used in
-Stage 1 (HMG-CoA reductase)
-Stage 2
-Stage 3 (squalene synthase)
-Stage 4 (squalene monoxygnase
-Stage 1: 2 NADPH
-Stage 2: 3 ATP
-Stage 3: 1 NADPH
-Stage 4: 1 NADPH
3 Inherited disorders of Cholesterol Biosynthesis:
1. Chondrodysplasia punctata
2. Latherosterolosis
3. Smith-lemli-Opitz syndrome
What are the cholest biosynth inherited disorders associated with?
Developmental malformities
What is the problem in these disorders?
Low cholesterol levels - lack of Hedgehog morphogens b/c they are made by post-transl. attachment of cholesterol.
What is the main regulatory target in cholesterol biosynth?
HMG-CoA Reductase
3 levels of Regulating HMG-CoA reductase:
1. Gene Transcription
2. Proteolysis
3. Phosphorylation
How is gene transcription of HMG-CoA reductase regulated?
By SREBPs
Sterol Regulatory Element Binding Proteins
Where are SREBPs normally located? When is this the case?
In the ER - when cholesterol is high (biosynthesis unnecessary)
What happens to SREBPs when serum cholesterol gets low?
SCAP (on ER membrane) senses low levels; it travels to Golgi w/ SREBP, then cleaves SREBP
What part of SREBP gets cleaved; where does it go?
N-terminus -> goes to the nucleus to bind the SRE for HMG-CoA reductase.
What is SRE?
Sterol Regulatory Element
Result of SREBP binding to SRE?
Activated transcription of HMG-CoA reductase hence increased cholesterol biosynth.
What causes proteolysis of HMG-CoA reducatase?
metabolites of cholesterol
What 2 things do Cholesterol metabolites inhibit?
What do they ACTIVATE?
-HMGCoA reductase (proteolysis)
-Extracellular uptake from LDL via receptor mediated endocytos.
-Activates ACAT for esterifictn
Phosphorylated HMG-CoA is ____
Dephosphorylated HMG-CoA is ____
Phosph = inactive

Dephosph = active
What stimulates HMG-CoA phosphorylation/dephosphoryltn?
Glucagon -> phosphorylate

Insulin -> dephosphorylate
How does glucagon stimulate phosphorylation of HMG-CoA red?
Via AMP-activated protein kinase
How does insulin stimulate dephosphorylation of HMG-CoA rd?
Via HMG-CoA Reductase Phosphatase
What are Statins?
Competitive Inhibitors of HMG-CoA reductase
What are the 4 Statins?
-Compactin
-Simvastatin (Zocor)
-Pravastatin (Pravachol)
-Lovastatin (Mevacor)
What are Statins used for?
To treat familial hypercholesterolemia
What pleiotropic effect is exhibited by statins?
Improved endothelial function via increased ENOS activity -
is how Viagra was discovered.
End product of cholesterol is:
Bile acids
Where are bile acids made? From what?
In liver from cholic acid
What is cholic acid?
Derivative of Cholesterol that is more soluble - 24 Carbons and 3 OH
What is the function of bile acids?
To emulsify fats in prep for pancreatic lipase
What happens to bile acids after release from gallbladder to intestine?
Reabsorbed - synthesis is not enough to meet physiolog demands.

Tavallinen influenssarokote ja Pandemrix verrattuna

http://www.skane.se/Public/Skaneportalen-extern/Halsaovard/Aktuellt/Dokument/Fakta%20om%20vaccin%20och%20Pandemrix.pdf

Narkolepsiaa Pandemrixin adjuvantista

DN.se kirjoittaa tänään 1 helmikuuta 2011:

http://www.dn.se/nyheter/vetenskap/vaccinering-kan-ge-narkolepsi

Vaccinet har stoppats i Finland medan den svenska Socialstyrelsen avvaktar med sitt beslut.

– Man måste se den här studien som en del av en stor utredning som nu genomförs i Europa, säger Anders Tegnell, avdelningschef på Socialstyrelsen, till TT.

Den finländska studien visar på en nio gånger förhöjd risk att få narkolepsi för barn som vaccinerats med Pandemrix-vaccinet.

Nästan alla som vaccinerats i Sverige den här vintern har fått en annan typ av vaccin, ett vanligt säsongsinfluensavaccin som också ger skydd mot svininfluensa.

I Sverige har Läkemedelsverket fått in 60 rapporter om narkolepsifall från sjukvården där man misstänker att det finns ett samband med vaccinationen. Läkemedelsförsäkringen har tagit emot 19 anmälningar med krav om ersättning till barn och unga som drabbats av den obotliga sjukdomen. Ännu har inga pengar betalats ut eftersom utredningar om sambandet fortfarande pågår i hela EU.

Massvaccinationen i Sverige förra vintern räddade med stor säkerhet ett antal liv och gjorde så att många slapp undan svåra sviter efter svininfluensa. Hur många får vi aldrig veta. Framför allt visade sig vaccinets skyddseffekt bra hos små barn.

Men som det verkar kan också ett stort antal barn i Sverige och Finland ha drabbats av livslångt lidande på grund av vaccinationerna.

– Det finns två vågskålar och i den ena ligger detta mycket tråkiga och i den andra ligger de positiva effekter vaccinet har haft. Det är oerhört svårt att värdera om det var rätt eller fel, säger statsepidemiolog Annika Linde vid Smittskyddsinstitutet.

– Det är så oerhört trist att detta hände och det finns ingen som på ett bra sätt kan gottgöra de barn och familjer som har drabbats av det här. Vi måste naturligtvis ha det i åtanke i framtida planering. Men beslutet att köpa vaccin var definitivt ett beslut som jag tror att vi skulle göra om, säger hon.

Totalt har cirka 31 miljoner människor vaccinerats med Pandemrix mot svininfluensa i Europa.

Det märkliga är att endast barn i Sverige, Finland och Island verkar ha drabbats av narkolepsi efteråt. Orsaken till detta är än så länge ett mysterium men en tänkbar förklaring skulle kunna vara att barnen haft en pågående influensainfektion vid vaccinationstillfället. Genetiska faktorer kan också ha bidragit till sjukdomsförloppet.

BBC kolesterolista

( Suomennan myöhemmin...)

World 'failing to treat high cholesterol'
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Most people around the globe with high cholesterol are not getting the treatment they need, claims the largest ever study of 147m people.

High levels of the blood fat are linked with cardiovascular disease, the world's biggest killer, which takes 17m lives a year.

The report in the Bulletin of the World Health Organization says too few people are put on cholesterol-lowering drugs.

The data, spanning a decade, is from England, Scotland and six more nations.

Between 1998 and 2007 information on cholesterol levels and prescribing patterns were gathered for England, Germany, Japan, Jordan, Mexico, Scotland, Thailand and the US.

Start Quote

Effective medication coverage for control of high cholesterol remains disappointingly low”

End Quote Dr Gregor Roth Co-author of the WHO report

The analysis found many at-risk people in middle-income and western countries alike are not on cheap and widely available statin drugs that would substantially cut their risk of heart attack and stroke.

The report authors, which included Dr Gregory Roth from the Institute for Health Metrics and Evaluation in the US, say: "These findings support the growing recognition that cardiovascular diseases are not merely 'diseases of affluence' and that some middle-income countries are beginning to face a double burden of both chronic and communicable diseases."

Global issue

For example, in Thailand 78% of adults surveyed, who were found to have high cholesterol, had not been diagnosed, while in Japan, 53% of adults were diagnosed but remained untreated.

Although England fared slightly better, in 2006, when its snap-shot was undertaken, over two-thirds of people remained undiagnosed and around a fifth were diagnosed but untreated.

Mexico did the best, diagnosing and treating nearly 60% of cases.

Experts stress that things may have moved on since the data was gathered.

For example, England last year announced a mass programme where every person aged 40 to 74 would be offered a cholesterol check by the GP in a bid to reach those that had previously been missed.

But certainly there is still more progress that could be made on a global scale, says Dr Roth.

He said: "Cholesterol-lowering medication is widely available, highly effective and can play an essential role in reducing cardiovascular disease around the world.

"Despite these facts, effective medication coverage for control of high cholesterol remains disappointingly low."

Not all patients with high cholesterol will need drug treatment. Lifestyle measures like taking regular physical activity and eating a healthy diet, as well as giving up smoking, can help prevent heart disease and stroke.


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