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Why does oxidation accelerate at 37 °C rather than proceeding linearly?

Asked 8 Jul 2024Modified 21 months agoViewed 46k times
This question was marked as a duplicate of Does fibrillation dominate for survodutide held at 4 °C?Closed 22 Jul 2024. It remains here because the answers below are specific to how it was asked.
31

Concretely: oxidation · 37 °C.

This is one of those things that everyone repeats and nobody derives.

This matters practically, not just academically, because it changes what I would do next.

Is the standard explanation correct, and if so, what is the evidence for it?

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NK
askednils_karlberg9.4k158 Jul 2024
5Same question here after a warm delivery, so I am following this. – a_lindgren 8 months ago
4Worth saying whether the vial has been opened, because that starts a different clock. – RP_C18 6 months ago
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5 Answers

Accepted answer first, then by votes
166

Accepted answer

Because temperature enters the rate constant through an exponential, so equal steps in temperature multiply the rate instead of adding to it. Arrhenius puts the rate proportional to exp(−Ea/RT); the working approximation is a doubling per 10 K, which takes 5, 15, 25 and 35 °C to multipliers of 1, 2, 4 and 8. The steps in temperature are equal and the steps in rate are not, and that is the whole of the observation. At 37 °C the same rule gives about 9.2 times the refrigerated rate, and another 10 K would roughly double it again. Met and Trp take up oxygen sixteen daltons at a time, and the oxidised species is more polar, so on a reversed-phase column it elutes ahead of the parent rather than behind it. Ea differs by route, so the ranking of routes changes with temperature too — which is why accelerated data extrapolates badly and why nobody should read a 40 °C study as a fast version of a 5 °C one.

The relevant point is that a mass shift of plus one dalton is deamidation and plus sixteen is oxidation, so degradation is often visible in a mass spectrum if anyone looks.

Oxidation targets methionine, cysteine and tryptophan, adding sixteen daltons per oxygen. It is catalysed by trace metals and promoted by dissolved oxygen and by light.

Light exposure matters for tryptophan-containing sequences and for anything with a chromophore. Amber vials and a closed box are free mitigations.

Metal-catalysed oxidation of methionine is documented across peptide and protein formulations and is why chelators appear in some formulations.

Sequence determines which pathways apply, so general statements are general.

A mass spectrum names the pathway. Plus one, plus sixteen, minus eighteen.

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MO
answered · acceptedmarta_okonkwo190k25819 Aug 2024
8Adding a vote because this deserves more of them. – t_oyelaran 2 months ago
7Two lots stored differently, reassayed at a year — the difference was smaller than I expected. – birk_nordahl 8 days ago
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65

This is answerable from the chemistry rather than from anecdote, which is unusual and welcome.

Adsorption onto glass and plastic is significant at low concentrations — micrograms per millilitre — and negligible at milligrams per millilitre. It is the usual explanation for an apparent loss in a dilute preparation.

The relevant detail is that freeze-thaw cycling drives aggregation through concentration at the ice interface and pH shifts as buffer components crystallise out at different rates. Each cycle costs something.

Apparent loss in a dilute preparation is usually adsorption rather than degradation and is worth ruling out first.

Sequence decides which pathways are even available. Check the residues.

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C8
answeredcoldpack_8850k3730 Aug 2024
49

Start with the sequence, because which pathways are available depends on which residues are present.

Aggregation is physical: peptides unfold at air-liquid interfaces and associate. Shaking maximises that interface, which is why swirling and shaking produce visibly different outcomes on the same vial.

A mass spectrum resolves most of this: minus eighteen is dehydration or succinimide, plus one is deamidation, plus sixteen is oxidation, and an unchanged mass with a shifted retention time is an isomer.

Nothing here is medical advice, and research-use compounds are not approved for human use.

Swirl, never shake. Aggregation is a handling problem more than a time problem.

edited 4 Aug 2024 by ines_brandt — updated for the 2026 guidance change

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IB
answeredines_brandt113k25727 Jul 2024
This should be in the site help pages rather than buried in an answer. – nkem_obiora 2 months ago
8I would add a sentence about light, since tryptophan-containing sequences care. – Dr_Yusuf_Adeyemi 23 days ago
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39

The underlying point is that asparagine and glutamine are the deamidation risk, and methionine is the oxidation risk.

Hydrolysis cleaves the backbone, most readily at aspartate-proline and aspartate-glycine sequences, and is acid-catalysed. In a dry solid it barely proceeds at all.

Adsorption losses at low concentrations are quantified in formulation studies and are the reason carrier proteins are used in dilute preparations.

At dilute concentrations, suspect adsorption before you suspect chemistry.

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MO
answeredmarta_okonkwo190k2588 Aug 2024
8Any published figure for how much a collapsed cake actually retains? – ruaidhri_o_shea 7 months ago
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1

Answering this needs the physical state, since a dry powder is protected from most of these and a solution is protected from none.

Deamidation converts asparagine or glutamine to the corresponding acid via a succinimide intermediate, adding one dalton. It is base-catalysed, accelerates above neutral pH and is the dominant aqueous pathway for many peptides.

Deamidation via the succinimide intermediate is well characterised, with sequence-dependent rates highest for asparagine-glycine motifs.

Cold, dry, dark, still. Those four words cover most of the mitigation.

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RP
answeredrhian_prydderch23k272 Nov 2024

Your answer

Ask PeptideStack is a static archive. Posting is closed, but the norms are worth stating: answer the question that was asked, show your working, cite the trial or the certificate, and say plainly where the evidence runs out.

Not medical advice. Research-use-only compounds are not approved for human use.