View Full Version : Malaria


SB_UK
07-24-15, 05:15 AM
Plasmodium falciparum - lifecycle

mosquito stage
-> liver stage -> red blood cell stage [expansion]
-> mosquito stage

Liver and Red blood cells - the 2 sites which can't use ketones as fuel.
Almost all tissues an cell types are able to use ketones as fuel except for liver and red blood cells. (https://books.google.co.uk/books?id=3FNYdShrCwIC&pg=PA431&lpg=PA431&dq=ketone+body+red+blood+cell+liver&source=bl&ots=4BY27--ZQF&sig=5PswtHJMzTVJTFE1hsowPy0CbbE&hl=en&sa=X&ved=0CEYQ6AEwBWoVChMI3q31xrDzxgIVCWvbCh1xVAQN#v=on epage&q=ketone%20body%20red%20blood%20cell%20liver&f=false)
That's too much of a co-incidence.

Malaria is considered to have provided us with the single greatest selective pressure on the human genome (eg ).

eg (http://hmg.oxfordjournals.org/content/11/20/2469.full)malaria has exerted a strong selective pressure on the human genome. Liver - can use fat
Red blood cells - anaerobic glycolysis

However ! plasmodium falciparum contains mitochondria.

http://ars.els-cdn.com/content/image/1-s2.0-S0005272801002377-gr10.gif
Fig. 10. Possible electron transfer chain in mitochondria of erythrocytic stage P. falciparum. Reducing equivalent from dihydroorotate is transferred to oxygen via classical respiratory pathway and to fumarate via QFR activity of complex II
reference (http://www.sciencedirect.com/science/article/pii/S0005272801002377)


FUMARATE -> SUCCINATE



Noting that


Complex II is pushed in the opposite direction in aerobic metabolism


SUCCINATE ->FUMARATE


https://upload.wikimedia.org/wikipedia/commons/thumb/8/89/Mitochondrial_electron_transport_chain%E2%80%94Etc 4.svg/600px-Mitochondrial_electron_transport_chain%E2%80%94Etc 4.svg.png

and



Note reversible

http://www.mikeblaber.org/oldwine/BCH4053/Lecture38/step06.gif

AND (from yesterday)

[b-hydroxybutyrate operates] by a complex II–dependent mechanism that leads to improved mitochondrial respiration and ATP production.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC193668/
http://journal.frontiersin.org/article/10.3389/fphys.2014.00260/full

When ketone bodies are delivered to the peripheral organs, β-OHB is oxidized back to AcAc by the mitochondrial D-β-hydroxybutyrate dehydrogenase (Figure 2 (http://journal.frontiersin.org/article/10.3389/fphys.2014.00260/full#F2)). The utilization of ketone bodies requires an enzyme not present in the ketone body biosynthetic pathway, succinyl-CoA:3-oxoacid-CoA transferase (also known as SCOT), which converts AcAc to acetoacetyl-CoA.
http://www.frontiersin.org/files/Articles/101953/fphys-05-00260-HTML/image_m/fphys-05-00260-g002.jpg

Malaria parasite
Mitochondria - Complex II

FUMARATE -> SUCCINATE

Human beings (not rbc/liver)
Mitochondria - Complex II and Citric acid cycle (CAC)

SUCCINATE -> FUMARATE
ie FAD -> FADH2 in CAC and then FADH2 -> FAD in ELECTRON TRANSPORT CHAIN for standard oxidative phosphorylation in aerobic metabolism - and the opposite occurs (an anaerobic beast !) in malaria parasite ?

NOTE

SUCCINATE -> <- FUMARATE is reversible.

-*-

So ... ... ... does a switch to ketone body metabolism reverse an essential biosynthetic process in the malarial parasite's lifecycle.

SB_UK
07-24-15, 05:27 AM
Aaaaghhhh !!!

http://www.addforums.com/forums/showpost.php?p=1253075&postcount=74

quinine -> hypoglycaemia

SB_UK
07-24-15, 05:30 AM
WHAT is QFR ?
QFR, quinol–fumarate reductase

SB_UK
07-24-15, 05:32 AM
What's the treatment for malarial infections ?

Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.

[wikiP/chloroquine]

SB_UK
07-24-15, 05:34 AM
And finally - what else is chloroquine ?

DMARD

As it mildly suppresses the immune system (https://en.wikipedia.org/wiki/Immune_system), it is used in some autoimmune disorders (https://en.wikipedia.org/wiki/Autoimmune_disorder), such as rheumatoid arthritis (https://en.wikipedia.org/wiki/Rheumatoid_arthritis) and lupus erythematosus (https://en.wikipedia.org/wiki/Lupus_erythematosus).
[wikiP/chloroquine]

Meaning ?

An underlying metabolic shift from carb to ketone body usage.

Ketone bodies generated via one of many mechanisms.

SB_UK
07-24-15, 05:49 AM
In humans Chloroquine inhibits thiamine (https://en.wikipedia.org/wiki/Thiamine) uptake.[wikiP/chloroquine]

Thiamine
TPP (who remembers their cofactors ???)

TPP - inhibited.

So - we want this to inhibit carbohydrate metabolism.

-*-

Yay!!!

TPP is required for carbohydrate metabolismhttps://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/krebs.htm

because TPP is required for carbohydrate metabolism, and the brain depends on glucose metabolism for energy. There is another way !

SB_UK
07-24-15, 06:24 AM
who remembers their cofactors ?


VITAMINS AND COENZYMES Vitamin Coenzyme Reaction type Coenzyme class SOURCE: Compiled from data contained in Horton, H. R., et al. (2002). Principles of Biochemistry , 3rd edition. Upper Saddle River, NJ (http://www.chemistryexplained.com/knowledge/Upper_Saddle_River__New_Jersey.html): Prentice Hall. B 1

(Thiamine) TPP Oxidative decarboxylation (http://www.chemistryexplained.com/knowledge/Oxidative_decarboxylation.html) Prosthetic group B 2
(Riboflavin (http://www.chemistryexplained.com/knowledge/Riboflavin.html)) FAD Oxidation/Reduction Prosthetic group B 3
(Pantothenate (http://www.chemistryexplained.com/knowledge/Pantothenic_acid.html)) CoA - Coenzyme A Acyl group transfer Cosubstrate B 6
(Pyridoxine) PLP Transfer of groups to and from amino acids Prosthetic group B 12
(Cobalamin) 5-deoxyadenosyl cobalamin Intramolecular rearrangements Prosthetic group
Niacin NAD + Oxidation/Reduction Cosubstrate
Folic acid Tetrahydrofolate One carbon group transfer Prosthetic group
Biotin Biotin Carboxylation Prosthetic group
Read more: http://www.chemistryexplained.com/Ce-Co/Coenzyme.html#ixzz3gnjnLawY


FAD -- REDOX

-*-

In anaerobes, other less-oxidizing substances such as sulfate (SO42−), nitrate (NO3−), sulphur (S), or fumarate (https://en.wikipedia.org/wiki/Fumarate) are used.
https://en.wikipedia.org/wiki/Anaerobic_respiration

-*-

P. falciparum-infected erythrocytes and free parasites incorporated [2,3-14C]fumarate into the nucleic acid and protein fractions.http://www.jbc.org/content/286/11/9236.full

-*-

Citric acid cycle [only in presence of mitochondria and aerobic metabolism]

succinate -> fumarate -> malate

-*-

NOT YET

What do I want the answer to be ?
A mechanism of starving less energetically efficient processes through the acquisition of more energetically efficient processes - ie shifting essentially weak anaerobic carb based into strong aerobic ketone based metabolic pathways - in the process protecting human beings from infectious diseases.
One fuel [carb] - less efficient and consistent with growth/mitosis - therefore supports cancer/auto-immune disease/infectious disease growth
One fuel [ketone] - more efficient and consistent with maintenance (growth inhibitory) - physical disease protective

So - 'fuel type to ketone' and 'learning to cerebellar automatising' would represent the key genome conferred and neurally conferred mechanisms to build HEALTHY body and HEALTHY brain/mind.

SB_UK
07-24-15, 06:48 AM
FUMARATE AGAIN

http://www.jbc.org/content/286/11/9236.full
Unlike its human host, P. falciparum lacks the de novo purine biosynthetic pathway and is hence completely dependent on the purine salvage pathway to meet its purine nucleotide requirements ... ...

http://www.jbc.org/content/286/11/9236/F1.medium.gif
Purine salvage pathway in the intraerythrocytic P. falciparum. Adenosine and hypoxanthine salvaged from the host are converted to IMP, which then branches out to form AMP and GMP. Excess AMP is deaminated back to IMP to constitute purine nucleotide cycle. A molecule of fumarate is also generated for each molecule of AMP. The arrow and the question mark have been put in to emphasize that the reutilization pathway of fumarate has not been elucidated.

SB_UK
07-24-15, 07:17 AM
SUCCINATE -> FUMARATE -> MALATE in citric acid cycle
SUCCINATE -> FUMARATE in electron transport chain

FUMARATE -> SUCCINATE in malaria parasite Complex II (QFR)

A -> AMP + GMP + FUMARATE
Essential for replication of malarial parasite.

The arrow and the question mark have been put in to emphasize that the reutilization pathway of fumarate has not been elucidated. In aerobic respiration, the tricarboxylic acid cycle is pivotal to the complete oxidation of carbohydrates, proteins, and lipids to carbon dioxide and water. Plasmodium falciparum, the causative agent of human malaria, lacks a conventional tricarboxylic acid cycle and depends exclusively on glycolysis for ATP production. However, all of the constituent enzymes of the tricarboxylic acid cycle are annotated in the genome of P. falciparum, which implies that the pathway might have important, yet unidentified biosynthetic functions. Here we show that fumarate, a side product of the purine salvage pathway and a metabolic intermediate of the tricarboxylic acid cycle, is not a metabolic waste but is converted to aspartate through malate and oxaloacetate.FUMARATE -> MALATE -> OXALOACETATE -> ASPARTATE in malaria parasite
FUMARATE -> MALATE -> OXALOACETATE in Citric acid Cycle

-*-

From (https://en.wikipedia.org/wiki/Glycolysis#Interactive_pathway_map)

GLUCONEOGENESIS (essential in ketosis)
OXALOACETATE -> PHOSPHOENOLPYRUVATE (IN GLYCOLYSIS)
UNI-DIRECTIONAL

So ... ... ...

FUMARATE -> MALATE -> OXALOACETATE -> ASPARTATE in malaria parasite
OXALOACETATE -> PHOSPHOENOLPYRUVATE (IN GLYCOLYSIS) in GLUCONEOGENESIS

2 STAGES OF MALARIAL PARASITE.
1. LIVER
2. RED BLOOD CELL

A. LIVER - PIVOTAL (PRE RBC) WHERE PROLIFERATION OCCURS OF MALARIAL PARASITE
B. MALARIAL PARASITE - REQUIRES PURINE SALVAGE PATHWAY TO GROW (GENERATION OF NUCLEOTIDES)
C. MALARIAL PARASITE - REQUIRES OXALOACETATE -> ASPARTATE
D. HUMAN HOST (LIVER) - IN GLUCONEOGENESIS - REQUIRES OXALOACETATE -> PHOSPHOENOLPYRUVATE
E. LIVER EMINENTLY CAPABLE OF GLUCONEOGENESIS
F. LIVER WON'T USE KETONE BODIES

-*-

I think that works -

G. Regeneration of carbs by gluconeogenesis sequesters oxaloacetate which is rquired in P.falciparum proliferation via
This study, therefore, provides a biosynthetic function for fumarate hydratase, malate quinone oxidoreductase, and aspartate aminotransferase of P. falciparum.

Our 13C NMR experiments showed peaks corresponding to malate, aspartate, and pyruvate. This excludes a direct route of conversion of fumarate to aspartate, which is supported by the absence of a homolog of aspartase in the P. falciparum genome (7 (http://www.jbc.org/content/286/11/9236.full#ref-7)). So - solution ... ... ...
FUMARATE -> MALATE -> OXALOACETATE -> ASPARTATE in malaria parasite
OXALOACETATE -> PHOSPHOENOLPYRUVATE (IN GLYCOLYSIS) in GLUCONEOGENESIS
Hepatic dietary-based re-routing of oxaloacetate into gluconeogenesis to 'starve' Plasmodium falciparum of essential anabolic building blocks (aspartiate) - no replication within the liver - death.'

That does make sense.

-*-

Sugestion - extreme keto-adaption as malarial protective.
Malaria exposure as driver of (genomic selection) - ketogenic metabolism as the new 'us'.
Problem - evolutionariy wired through primitive reward system via sweet, umami and salt to eating foods which 'grow' the parasite.
Solution - complete human life-cycle to escape the primitive reward system - completes upon attaining wisdom.

-*-

Problems.
1. Increased oxaloacetate in ketosis could still support malarial parasite (oxaloacetate -> aspartate) growth
2. Sunccinate -> <- Fumarate is reversible - so in the ETC we still need to shunt fumarate -> succinate in order to provide succinate for the reverse direction ie f -> s must still occur in humans


However - definitely something to do with:
succinate -> fumarate -> malate -> oxaloacetate -> phosphoenolpyruvate or aspartate or citrate

It takes part in the: gluconeogenesis (https://en.wikipedia.org/wiki/Gluconeogenesis), urea cycle (https://en.wikipedia.org/wiki/Urea_cycle), glyoxylate cycle (https://en.wikipedia.org/wiki/Glyoxylate_cycle), amino acid synthesis (https://en.wikipedia.org/wiki/Amino_acid_synthesis), fatty acid synthesis (https://en.wikipedia.org/wiki/Fatty_acid_synthesis) and citric acid cycle (https://en.wikipedia.org/wiki/Citric_acid_cycle).[1] (https://en.wikipedia.org/wiki/Oxaloacetic_acid#cite_note-Lehn-1)
That's impressive.

SB_UK
07-24-15, 07:46 AM
A recent study that appeared while this manuscript was under revision reports that PfAAT inhibition is lethal to the parasite http://www.jbc.org/content/286/11/9236.full

oxaloacetate -> phosphoenolpyruvate <- gluconeogenesis
oxaloacetate -> aspartate <- essential for p. falciparum survival

Tantalisingly close.

Six essential amino acids and three nonessential are synthesized from oxaloacetate and pyruvate (https://en.wikipedia.org/wiki/Amino_acid_synthesis#Oxaloacetate.2FAspartate_Fami ly).

So - when 'starving' are you going to launch 'proliferation' or 'maintenance' programs?
Presumably - to mimic starvation - noting - "The origins of the ketogenic diet were the observations of Hippocrates in 500BC that fasting could reduce and even cure epileptic seizures (fasting is also a ketogenic state ... ..."

Proliferation - biosynthetic - amino-acid (originating from oxaloacetate/pyruvate -> the non-aromatic amino acids) and nucleotide (de novo + salvage pathways) shut down
and
Maintenance - aerobic respiration favoured.

oxaloacetate -> phosphoenolpyruvate <- gluconeogenesis
oxaloacetate -> aspartate <- essential for p. falciparum survival


Oxaloacetate, Pyruvate

Aspn
Met
Lys
Thr
Ala
Val
Leu
Iso

So - all cases (https://en.wikipedia.org/wiki/Amino_acid#/media/File:Amino_Acids.svg) covered if Met is considered a special case - because of its Sulphur group.

Point - really intimate connection between metabolism, nucleotide and protein

-*-

So [higher] maintenance <- oxaloacetate -> growth [primitive]
2 basic metabolic routes - lower organisms more dependent on primtive growth pathway than neural organisms - which are customised to existence within a non-growth, nonproliferative keto-adapted environment ?

>7 years nerves (brain) just want to stick around and re-connect - not to grow or decrease in number.

SB_UK
07-24-15, 08:50 AM
The gut's the 2nd brain.
The brain's the 2nd gut.

From carb intake (the primitve reward system cf Substantia nigra free dopamine production) to de novo acetate generation (the higher reward system cf Substantia nigra neuromelanin polymerized dopamine production).

Lunacie
07-24-15, 01:38 PM
I am missing something. What does this have to do with ADHD?

aeon
07-24-15, 01:55 PM
Thanks for this, I found it interesting in general, but also more specifically as a Type 2 diabetic, and then there were bio-spiritual angles I contemplated.

Lunacie, if you've never experimented with a ketogenic diet, I'll simply offer that for me, it had an interesting (positive) effect on the presentation of my ADHD-PI, though not to the level of my current meds (60mg/day extended release dextroamphetamine).

Cheers,
Ian

Lunacie
07-24-15, 02:56 PM
Thanks for this, I found it interesting in general, but also more specifically as a Type 2 diabetic, and then there were bio-spiritual angles I contemplated.

Lunacie, if you've never experimented with a ketogenic diet, I'll simply offer that for me, it had an interesting (positive) effect on the presentation of my ADHD-PI, though not to the level of my current meds (60mg/day extended release dextroamphetamine).

Cheers,
Ian

I didn't see any reference to ketogenic diet improving ADHD symptoms in
SB's posts.

Our family has been doing a modified keto diet for a couple of years because
my autistic granddaughter developed type 2 diabetes due to one of her meds.

We have been able to control the diabetes by using this diet, but decided to
stop giving this med.

We're back to coping with mood swings and some violence, but the diabetes
seems to be gone.

It's a balancing act, and we feel like we're tottering and ready to fall.
Hard choice, diabetes and life long complications or ... an unhappy, anxious
kiddo who lashes out and leaves her mom with bruises and bite marks.

So anyway, back to the topic, the keto diet is helping the diabetes, but not
the autism/anxiety/adhd.

Abi
07-24-15, 06:02 PM
Luna was it Risperdal that caused the diabetes?

Lunacie
07-24-15, 06:33 PM
Luna was it Risperdal that caused the diabetes?

Yes. The doc who first prescribed it told us it could cause this problem,
and that we'd need to have her blood sugars checked. But then he left
the practice for emergency medicine and apparently the partner doc
didn't realize this needed to be done. We didn't realize it either.

She was being tested to take part in a drug trial and alerted us to her
high blood sugars.

Unfortunately, this is the only med that helped with her anxiety and her
mood swings. So tough call on whether to keep giving it ... or not give it.