Скачать или смотреть Chemistry of the TCA (TriCarboxylic Acid)/citric acid/Krebs cycle

One of those "in too deep" videos I made where I allow myself to totally geek out beyond the level of detail that I give my class – this one a deep dive into the chemical logic of the TCA. Thanks for letting me geek out here :)

Much of it involves carbonyl chemistry. Here's more on that: https://bit.ly/coolcarbonylchem

·      Names: TriCarboxylicAcid cycle (TCA), Citric Acid Cycle (CAC), Krebs cycle
·      Serves a central hub of metabolism, which lots of pathways feed into and out of
·      Takes place in mitochondrial matrix, with succinate dehydrogenase in the inner mitochondrial membrane (remember it’s CII of the ETC!!!)
o   Since it’s producing NADH in the matrix, no shuttling is required
·      2C are removed per cycle (as CO2) → these 2 are added back as acetyl-CoA, which joins with oxaloacetate (4C) to form citrate (6C)
·      Per cycle: + 3 NADH, + 1 FADH2, + 1 GTP (or ATP, depending on isoform of succinate dehydrogenase used), -2 CO2
·      The first part of the TCA involves the decarboxylations, the second part is mainly rearranging things
·      At succinate, the molecule is symmetrical, so you stop being able to distinguish between the original C2 and the original C5
·      Key steps:
o   Isocitrate dehydrogenase (IDH): here you lose 1C and gain 1 NADH
o   α-ketoglutarate dehydrogenase complex: here you use a CoA, lose 1C and gain 1 NADH
o   succinyl-CoA synthetase: here you gain 1 GTP (or 1 ATP)
o   succinate dehydrogenase (this is CII of the ETC!): here you gain 1 FADH2
o   Malate dehydrogenase (MDH): here you gain 1 NADH
 
 
·      Some steps are “setup” steps, setting the stage to make subsequent reactions more favorable
o   Decarboxylation of a β-keto acid is more favorable than decarboxylation of an α-keto acid
§  You can make subsequent decarboxylation more favorable by first forming a β-keto acids
·      E.g. aconitase creates β-keto acid that’s subsequently decarboxylated by isocitrate dehydrogenase
o   Ketones are more stable than enols
§  You can make subsequent decarboxylations and phosphate transfers more favorable by first forming β-keto acids and phosphoenols
·      E.g. pyruvate kinase in glycolysis: enolase makes phosphoenolpyruvate (enol trapped by phosphate) that transfers phosphate group to ADP to make ATP and form pyruvate (ketone)

• Can be used in full or in parts, for both catabolism & anabolism
o Catabolic when used in its entirety → fully oxidizes acetyl-CoA (such as is made from pyruvate)
 Produces the bulk of NADH (and FADH2) from glucose → leads to bulk of ATP that can be produced from glucose catabolism (i.e. most of the energy from glucose does NOT come from glycolysis, but rather it comes from oxphos from electron carriers from the TCA)
o Lots of anabolic functions since it can interconvert 4-6 C intermediates that can be used as building blocks for different molecules
 Acts like a roundabout, but you’ve got to put more in if you take things out (and acetyl-coA does not count!!!!!)
• Oxaloacetate needs to be present for acetyl-CoA to come in – If you take ANY intermediate out of the pathway you won’t have oxaloacetate, UNLESS you put something more than 2 C in

• Anaplerotic reactions are reactions that regenerate pathway intermediates
o For something to be anaplerotic to the TCA, it must put in more C than get taken out (more than 2C)
 You lose 2C (as 2 CO2) per turn of TCA cycle, so for humans, must add something more than 2C to keep it going
• The glyoxylate shunt allows plants, bacteria, fungi, & protists to bypass the need for more than 2C compounds. It lets them sustainably synthesize oxaloacetate (and thus glucose) with just acetyl-CoA (e.g. from fats). We mere humans don't have this metabolic superpower...
o Since oxaloacetate (technically malate…) from the TCA can be used to make glucose, things that are anaplerotic for the TCA can be called glucogenic
• You need to go around the decarboxylation part of the cycle 1 time per 2C
o E.g. if you put oxaloacetate (4C), you’ve gotta go around the full circle twice; citrate (6C), 3 times, α-ketoglutarate ~2.5 (since you’re coming in midway, past the decarboxylations)


Recommended reading:

https://chem.libretexts.org/Bookshelv...

Organic Chemistry A Tenth Edition by John McMurry, Chapter 22: Carbonyl Alpha-Substitution Reactions and Chapter 23: Carbonyl Condensation Reactions, OpenStax https://openstax.org/details/books/or...

More on nucleophiles and electrophiles: http://bit.ly/nucleophilefiles  

Much more on all sorts of metabolic stuff: https://bit.ly/bbmetabolism & https://www.youtube.com/playlist?list...

more about all sorts of things: #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0 or search blog: http://thebumblingbiochemist.com