10:01:27 From Thomas Hutchinson to Everyone : Just a reminder:  a number of people seem to no realize that they’re not muted!  I’m not sure of the reason, but on joining I noticed that my own notebook wasn’t muted, as it usually is when joining.
10:02:10 From Maria Korchagina to Everyone : Yes! Sorry, I might have said something loudly. :)
10:02:19 From Marco Cosentino Lagomarsino to Everyone : This depends on the meeting settings… maybe the organisers can change that, to avoid future incidents.
10:06:20 From Rachel Gregor to Everyone : Could we put the Slack invite link here as well? Thanks!!
10:09:33 From Roderich Römhild to Everyone : When looking at the videos in the reference section, I started wondering what is the difference of electrochemistry and electron chemistry. Perhaps someone has a thought there.
10:10:00 From Terry Hwa to Everyone : This should be the invitation link

https://join.slack.com/t/ucsd-kjq7773/shared_invite/zt-kyv3eqgy-bffo3wcrpyadn6LeyuBYcQ
10:11:59 From Rachel Gregor to Everyone : @Terry Thank you!!
10:18:33 From Matthias Hülsmann to Everyone : does transport coupled phosphorylation generally require bigger proteins than substrate level phosphorylation? (because of trans-membrane transport processes)
10:26:31 From Terry Hwa to Everyone : @matthias: i am waiting for him to provide specific example of the two modes first.
10:28:02 From Roni Saiba to Everyone : @matthias it may also be the case that there smaller subunits can make larger complexes in transport coupling. It should become clearer once Andrew provides examples.
10:30:30 From Avi Flamholz to Everyone : hey all - I wasn’t here last week, but I want to point people to these two papers that derive a more detailed expression underlying the rate-yield tradeoff.
10:30:38 From Avi Flamholz to Everyone : (1) Beard & Qian 2007 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000144
10:31:30 From Roni Saiba to Everyone : I recall someone sharing this paper.
10:31:38 From Roni Saiba to Everyone : I actually have it saved
10:32:07 From Arvind Murugan to Everyone : Avi, someone also shared a paper by you that we all found useful .. one that writes the flux as a product of three things
10:33:03 From Avi Flamholz to Everyone : (2) Jin & Bethke 2007 derives the same relation from transition-state theory https://www.ajsonline.org/content/307/4/643
10:33:27 From Matthias Hülsmann to Everyone : Thanks, I was basically wondering, if, because substrate level phosphorylation does not require transmembrane transport and can therefore be carried out by a smaller enzyme, it might quite generally be the more ‘proteome efficient’ way of energy generation? (and therefore allow the highest energy conservation fluxes - as in overflow metabolism)
10:34:36 From Ramis Rafay to Everyone : Shouldn't the signs for the potential be reversed for electron acceptor?
10:35:13 From Terry Hwa to Everyone : Thanks Matthias. I do not know enough about proteins to know how catalytic rate relates to protein sizes. I imagine it’d have sth to do with how “easy” it is to perform a reaction.
10:36:20 From Vadim Patsalo to Everyone : can we please mute the 1858* phone user, high-pitched noise coming though?
10:36:23 From Avi Flamholz to Everyone : @matthias I don’t think there is a consistent relationship with size. There are some nice summaries of other trends in enzymatic parameters, e.g. this paper by my late friend Arren. https://pubs.acs.org/doi/abs/10.1021/bi2002289
10:36:52 From Avi Flamholz to Everyone : @matthias - the main trend, according to this more recent review, is the class of the reaction. like terry said - the chemistry has a big effect on the rate.
10:37:15 From Avi Flamholz to Everyone : https://pubs.acs.org/doi/10.1021/acs.chemrev.8b00039
10:37:28 From Zachary Landry to Everyone : This is an excellent review on redox in the environment: https://science.sciencemag.org/content/320/5879/1034.full
10:39:49 From Matthias Hülsmann to Everyone : @terry and @avi, thanks so much for sharing
10:40:47 From Avi Flamholz to Everyone : also @matthias worth noting that the underlying data for these meta-analyses are a very sparse subset of “all enzymes” since someone needs to do tens-hundreds of experiments to get the kinetic parameteers
10:41:24 From Terry Hwa to Everyone : @avi…  and in the same condition for comparison
10:42:32 From Roderich Römhild to Everyone : In the yellow combination, would then the reverse reactions occur?
10:52:48 From Ramis Rafay to Everyone : Someone is unmuted
10:55:33 From Ramis Rafay to Everyone : @roderich, yes that one is spontaneous so it is possible to occur
10:58:20 From Avi Flamholz to Everyone : except for the assumption of unitary activity coefficients
10:58:35 From Avi Flamholz to Everyone : i.e. concentration = activity
11:04:30 From Roderich Römhild to Everyone : Thanks :)
11:05:06 From Ramis Rafay to Everyone : there is a pretty simple approximation used for the anabolic part given the average stoichiometric composition of biomass
11:05:31 From Avi Flamholz to Everyone : I assume you need to know the average oxidation state also @ramis?
11:07:02 From Matthias Hülsmann to Everyone : Can I ask… why isn’t a more reduced carbon substrate (methane, fatty acids) the preferred substrate (e.g. over glucose) - it seems there would be more energy available when oxidising methane compared to glucose (per mol C). Can someone clarify?
11:07:04 From Ramis Rafay to Everyone : @ Avi yes which can be calculated from that average composition where C:H:O:N is 1:1.8:0.5:0.2
11:07:36 From Ramis Rafay to Everyone : (normalized per carbon atom of course)
11:11:05 From Matthias Hülsmann to Everyone : Thanks for asking Terry, thanks for the reply Alfred
11:12:08 From Avi Flamholz to Everyone : @matthias this is an awesome question. methane is one kind of issue (not prevalent, volatile, oxidizes spontaneously) and lipids are another kind of issue. there is a mysterious trend where more reduced carbon atoms have higher redox potentials, which affects the feasibility/rate of using them with electron acceptors other than O2 (e.g. iron minerals). another proposed reason for sugars is that they are more densely-connected to the metabolic network, but this is a bit of reverse logic. I can post various papers on this topic if you are interested.
11:13:32 From Terry Hwa to Everyone : @avi: very interesting point. pls post.
11:14:11 From Matthias Hülsmann to Everyone : thanks avi! yes, I’d be very interested.
11:15:15 From Avi Flamholz to Everyone : here’s a paper from Adrian Jinich that highlights the “rich-get-richer” trend where more reduced carbons have higher redox potentials. I did virtually nothing for this paper, give him all the credit. https://journals.plos.org/ploscompbiol/article/comments?id=10.1371/journal.pcbi.1006471
11:16:49 From Avi Flamholz to Everyone : This is an independent line of research from soil science that uses this trend along with the rate/yield tradeoff to study which substrates (sugars, lipids, acids) are retained in aerobic vs. anaerobic soils. Tough read but beautiful work from Scott Fendorf’s group at Stanford. https://www.nature.com/articles/s41467-017-01406-6
11:18:36 From Avi Flamholz to Everyone : adrian’s most recent paper addresses the connectivity of the “redox reaction network” and highlights that sugars are energy-dense and well-connected in the network https://www.pnas.org/content/117/52/32910
11:20:10 From Avi Flamholz to Everyone : this is similar to Elad Noors PhD paper which shows that the known metabolic pathways are composed of shortest path walks between important biomass precursors. but this presumes that sugars are precursors e.g. of cell wall biosynthesis rather than explaining why sugars are used as such. https://www.sciencedirect.com/science/article/pii/S1097276510006672
11:22:42 From Matthias Hülsmann to Everyone : great stuff, thank you!
11:22:54 From Martina Dal Bello to Everyone : Thanks!!
11:23:22 From Ramis Rafay to Everyone : @Avi super interesting, thanks!
11:25:38 From Roderich Römhild to Everyone : How constant/variable is membrane potential?
11:33:12 From Avi Flamholz to Everyone : don’t many natural environments have pretty extreme pHs though/
11:33:18 From Avi Flamholz to Everyone : ?
11:34:58 From Ramis Rafay to Everyone : If the external environment has a very low pH, wouldn't it take a lot of work to overcome the gradient and push a proton outwards?
11:35:39 From Avi Flamholz to Everyone : *cyanobacteria do actually do intracellular proton pumping
11:35:42 From Ralf Steuer to Everyone : cyanobacteria have an internal membrane system
11:35:45 From Avi Flamholz to Everyone : (minor aside)
11:35:48 From Ralf Steuer to Everyone : right ;)
11:35:52 From Avi Flamholz to Everyone : hey ralf!
11:36:46 From Ralf Steuer to Everyone : [also: wrt extreme environments … here "outside" is the cytosol, I think most organism in extreme environments still have a reasonable internal pH]
11:39:05 From Terry Hwa to Everyone : thanks for everyone, avi especially, for leaving a lot of useful comments and references. To make this a bit more permanent, can I ask you to post these also on the slack channel ?
11:40:08 From Terry Hwa to Everyone : slack link:  https://join.slack.com/t/ucsd-kjq7773/shared_invite/zt-kyv3eqgy-bffo3wcrpyadn6LeyuBYcQ
11:41:02 From Terry Hwa to Everyone : pls feel free to open up additional channels of topics
12:01:09 From Mikhail Tikhonov to Everyone : How often are the two catabolic half-reactions coupled directly versus coupled via a carrier?
(Hope the question makes sense...)
12:02:27 From Rory Gordon to Everyone : Why are 4Fe4S clusters present in ferredoxins found in aerobic microorganisms?
12:08:54 From Rory Gordon to Everyone : Could this be explained by the oxidoreductases having drastically different binding interfaces/electron tunnelling routes for ferredoxins with 4Fe4S clusters compared ferredoxins with ferredoxins2Fe2S clusters?
12:18:00 From Matti Gralka to Everyone : if all the carbon goes from glucose to pyruvate, and then the pyruvate is used as an electron acceptor, where does the carbon for biosynthesis come from?
12:19:29 From Terry Hwa to Everyone : one part of the glucose influx is for energy generation, the rest for biomass synthesis. He is only talking about the energy generation part.
12:19:32 From Emily Zakem to Everyone : is it a fraction of the glucose?
12:19:50 From Emily Zakem to Everyone : @terry, thanks
12:21:08 From Matti Gralka to Everyone : ah I see, thanks Terry - I'll save the question of how those fractions are decided is for another day
12:22:43 From Terry Hwa to Everyone : yes, there should be a basic strategy to coordinate carbon flux for biomass vs carbon flux for biomass. I don’t think we currently understand the strategy of this coordination (as we may understand C/N coordination.)
12:23:15 From Martina Dal Bello to Everyone : Shouldn’t it depend (at least in part) on the concentration of end products?
12:23:23 From Avi Flamholz to Everyone : there is intramolecular reduction and oxidation
12:23:35 From Avi Flamholz to Everyone : the electrons are withdrawn from one part of the molecule and donated back to another
12:23:37 From Avi Flamholz to Everyone : conceptually
12:23:49 From Mikhail Tikhonov to Everyone : moving electrons within the same molecule can be energetically advantageous
12:24:07 From Terry Hwa to Everyone : the problem with this kind of global coordination is that you don’t (or the cell wouldn’t know) which end product to rely on.
12:28:53 From Melissa Fritz to Everyone : Is it that redox potential is tied to both the start and end? That it isn't the redox of just pyruvate, it's the redox potential of glucose to pyruvate, then pyruvate to lactate?
12:30:06 From Avi Flamholz to Everyone : yes. and conceptually the reason it’s not a circle is that you oxidize one carbon on glyceraldehyde (in the glycose -> pyruvate part) and then reduce a different carbon in the pyruvate -> lactate part
12:30:45 From Melissa Fritz to Everyone : Ah, thank you 
12:31:31 From Akorede Seriki to Everyone : As you go down a pathway, do metabolites get more ‘reduced’? And is there any advantage to being a very reduced compound?
12:32:43 From Avi Flamholz to Everyone : in glycolysis it becomes more oxidized as you go down the pathway since you are withdrawing e- to make NADH from NAD+
12:33:14 From Akorede Seriki to Everyone : Okay. Thanks!
12:33:30 From Avi Flamholz to Everyone : the advantage is that it is thermodynamically favorable to do so and the energy can be coupled to ATP synthesis
12:34:47 From Avi Flamholz to Everyone : if I remember (@ramis can correct me) the average oxidation state of biomass is about the same as glucose, so oxidizing glucose is a bit disadvantageous from this perspective - you will need to “re-reduce” the products for anabolism. but you need to do it to store energy
12:36:55 From Erik van Nimwegen to Everyone : Thanks Avi. So if I understand it correctly the redox potential is not just a function of the molecule, but also of where in the molecule you are going to put the election (or where you are taking it from). Did I get that right?
12:37:13 From Erik van Nimwegen to Everyone : electron.. not election, obviously.
12:37:52 From Avi Flamholz to Everyone : yes!
12:38:04 From Avi Flamholz to Everyone : the potential is a function of a PAIR of molecules
12:39:17 From Caroline Holmes to Everyone : Is it just a potential difference, between where the electrons are on the reduced and the oxidized molecules?
12:39:25 From Akorede Seriki to Everyone : So, in every pathway there must exist this ‘pair of molecules’? And at what point does the pathway ‘end’? Or is evergy just stored up somewhere till its ready to be used?
12:39:34 From Akorede Seriki to Everyone : energy**
12:40:14 From Avi Flamholz to Everyone : @caroline — yes, the free energy difference due to any redox reaction is determined by the difference in redox potential between the e- donor and acceptor like earlier in this talk
12:40:44 From Avi Flamholz to Everyone : it depends where the e- are coming from and where they are going (and the number of e- transfered)
12:41:09 From Avi Flamholz to Everyone : @akorde we are only talking about redox reactions here. not all pathways are doing redox.
12:41:18 From Arvind Murugan to Everyone : But, avi, the point more germane to Erik’s question is that even the potential of a *half* reaction depends on where on the molecule you are ripping the molecular from?
12:41:48 From Avi Flamholz to Everyone : the standard potential of the half reaction is a constant in reference conditions
12:42:04 From Erik van Nimwegen to Everyone : Yes. If I take an electron from X and put it in Y, I can still imagine doing that in different ways depending on WHERE in X the electron comes from, and where in Y it is going to go.
12:42:13 From Avi Flamholz to Everyone : it’s written this way so that we can compose two different half reactions
12:42:31 From Arvind Murugan to Everyone : Makes sense
12:42:48 From Avi Flamholz to Everyone : the potentials are written w.r.t a standard potential (e.g. standard hydrogen electrode) but this cancels out when you take the difference between the donor and acceptor
12:43:01 From Avi Flamholz to Everyone : I am not sure that was very clear
12:43:06 From Daan de Groot to Everyone : So I guess pyruvate can be both a reductor and an oxidator, and for these two different roles it has different standard potentials?
12:43:15 From Arvind Murugan to Everyone : Right - but when you write a half rxn, you are specifying where on the molecule you are adding an electron
12:43:28 From Avi Flamholz to Everyone : yes!
12:43:38 From Avi Flamholz to Everyone : it’s easiest to think about half-reactions
12:43:43 From Avi Flamholz to Everyone : e.g. pyruvate => lactate
12:43:48 From Avi Flamholz to Everyone : is a redox half reaction
12:43:57 From Avi Flamholz to Everyone : pyruvate + 2e- => lactate
12:44:05 From Avi Flamholz to Everyone : which specifies where on the molecule the e- go
12:44:30 From Mikhail Tikhonov to Everyone : yes, it's like the potential energy of a given electron in the molecule. Different electrons in the same molecule  will have different energies. Which is why we don't jsut arrange all compounds on a ladder of energy, because it matters which electron we're talking about. So talking about a given reaction instead, with a pair of compounds.
12:44:31 From Avi Flamholz to Everyone : once you consider this fixed, you need to know what the e- donor is (NADH, quinone, whatever) to calculate the free energy difference
12:45:47 From Daan de Groot to Everyone : @Mikhail, thanks, I think I understand it better now
12:46:49 From Avi Flamholz to Everyone : just to make it super concrete: if you instead consider pyruvate + 4 e- => h2o + propionate it will have a different potential than pyruvate + 2e- => lactate
12:47:06 From Avi Flamholz to Everyone : also notice that these reactions involve different numbers of electron
12:47:20 From Avi Flamholz to Everyone : but the potentials are written per-electron (average)
12:47:54 From Avi Flamholz to Everyone : so you don’t need to balance electrons between half reactions - it’s already a per e- potential
12:49:14 From Arvind Murugan to Everyone : Is there a redox biochemistry/metabolic biochemistry for real dummies (theoretical physicists)? Asking for a friend
12:50:08 From Avi Flamholz to Everyone : @arvind I wrote something here. Some of this material is covered at a very intro level. http://equilibrator.weizmann.ac.il/static/classic_rxns/classic_reactions/index.html
12:50:48 From Mikhail Tikhonov to Everyone : Thank you, Avi!
12:50:55 From Avi Flamholz to Everyone : I don’t know of a very good book - if someone has a recommendation I’d love to hear it.
12:52:04 From John Ciemniecki to Everyone : There are probably many, Avi’s examples are great, but two of my favorite intro books (~early graduate level) are Harold’s “The Vital Force” and Atkinson’s “Cellular Energy Metabolism and Its Regulation”
12:52:53 From Arvind Murugan to Everyone : Avi, this website looks great at first glance!   I’ll have to see if my physicist dummy friend understands it but it looks promising!
12:54:01 From Pranas Grigaitis to Everyone : @Arvind you might want to check out Alberty "Thermodynamics of Biochemical Reactions" as well. It discusses a lot of classical thermo concepts, so you're not completely lost at the first glance
12:59:25 From Avi Flamholz to Everyone : @boris one of the papers I posted above does a simplified version of what you suggest - jinich et al PNAS 2020
12:59:27 From Terry Hwa to Everyone : This paper may be relevant: https://www.pnas.org/content/117/52/32910
12:59:38 From Avi Flamholz to Everyone : yes - that one!
13:00:26 From Avi Flamholz to Everyone : there is a very limited set of reaction types that are catalyzed by known enzymes, probably limited by the functional groups in amino acids and the metals used
13:04:51 From Avi Flamholz to Everyone : @vadim - think about it as a superposition of two pathways. one pathway takes up glucose => lactate and another takes up glucose => biomass.
13:05:22 From Avi Flamholz to Everyone : the latter actually also needs nitrogen, sulfur, phorphorus and some vitamins, but the superposition is the main point
13:05:38 From Vadim Patsalo to Everyone : Sure, I understand that, but glucose->biomass also has NADH debt. How is that paid?
13:06:02 From Avi Flamholz to Everyone : if I remember correctly glucose to biomass is roughly redox balanced
13:06:13 From Avi Flamholz to Everyone : and to the extent that it is not, you can borrow NADH from the other pathway
13:06:22 From Avi Flamholz to Everyone : which changes the balance of the superposition
13:06:39 From Avi Flamholz to Everyone : would help to have a whiteboard
13:07:28 From Melissa Fritz to Everyone : thank you
13:07:30 From Lucas Le Nagard to Everyone : Thank you!
13:07:41 From Scott Gifford to Everyone : Thank you
13:07:41 From Gabriel Mullin-Manzanarez to Everyone : Thank you!