Hoiamides

Key takeaways

Hoiamides belongs to science; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Hoiamides to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Hoiamides from memory before moving on to harder problems.

Reference excerpt

The hoiamides are a class of small molecules recently characterized from isolations of secondary metabolites of cyanobacteria that feature a triheterocyclic system. Hoiamide A and B are cyclic while hoiamide C and D are linear. Hoiamide A and B demonstrate neurotoxicity by acting on mammalian voltage gated sodium channels, while hoiamide D shows inhibition of the p53/MDM2 complex. The hoiamides are promising therapeutic targets, making their total synthesis an attractive feat.

Structural class The structural class of hoiamides is charactered by an acetate extended and S-adenosyl methionine modified isoleucine unit. Central to the molecule is a triheterocyclic system made of two α-methylated thiazolines and one thiazole, and a highly oxygenated and methylated C-15 polyketide unit. The hoiamides are stereochemically complex structures, with hoiamide A and B exhibiting 15 chiral centers.

History Marine cyanobacteria obtained by SCUBA in Papua New Guinea offer abundant secondary metabolites. Sometimes called blue-green algae, marine cyanobacteria have long been recognized for their toxic effects. Since the 1930s, collections have been gathered from these organisms. Hoiamide A was isolated in 2009 from Lyngbya majuscula and Phormidium gracile through screening of cyanobacteria extracts using high throughput calcium and sodium ion influx assay in neocortical mouse neurons. Other groups have also found hoiamide A in M. producens and Phormidium gracile. Hoiamide B and C were isolated in 2010 from Symploca sp. and Oscillatoria cf. Hoiamide D was isolated in 2012 from Symploca sp. The total synthesis of hoiamide C was completed in 2011.

Bioactivity

Hoiamide A In mouse neocortical neurons, hoiamide A acts as a partial agonist to site two of the mammalian voltage gated sodium channel (VGSC). In electrically excitable cells VGSC allow the influx of sodium that causes the rising phase of the action potential. Hoiamide A stimulated sodium influx with EC50 of 1.7 micromolar in mouse neocortical neurons VGSC have at least six neurotoxic sites that act as targets for small molecules. By using a radioligand probe [3H]BTX known to bind to neurotoxic site two on the VGSC alpha subunit, a group found that hoiamide A must bind to site two as well, given its inhibition of [3H]BTX. A full agonist of VGSC site two, batrachotoxin, was then used to determine to what extent hoiamide A acted as an agonist. The experiments demonstrated that hoiamide A is a partial agonist because the maximum sodium influx hoiamide A binding caused was less than that of batrachotoxin. Another study found that hoiamide A stimulated capspase-3 activity, lactic acid dehydrogenase efflux, and nuclear condensation. These processes are specifically and uniquely involved in necrosis and apoptosis, suggesting that hoiamide A is involved neuronal death by both necrosis and apoptosis.

Hoiamide B Like hoiamide A, hoiamide B stimulated sodium influx in mouse neocortical neurons with an EC50 value of 3.9 micromolar. Because hoiamide B is so structurally similar to hoiamide A, research currently predicts that B is also a site 2 VGSC inhibitor. Though the mechanism of inhibition of calcium oscillations in mouse neocortical neurons is unknown for hoiamide A and B, both compounds potently suppress spontaneous calcium oscillations with EC50 values of 45.6 and 79.8 nanomolar, respectively.

Hoiamide C Hoiamide C exhibits a LC50 of 1.3 micromolar in brine shrimp toxicity assays. However, it does not disrupt spontaneous calcium ion oscillations. Because ethanol is used in storage of biological material, it is possible that hoiamide C may be an extraction artifact of hoiamide D.

Hoiamide D p53 protein is a well known tumor suppressor that regulates the cell cycle, DNA repair, and apoptosis by acting as a transcription factor. MDM2 is a murine ubiquitin ligase that downregulates p52 by various mechanisms. The binding surface of the two proteins is small, and the interaction is hydrophobic. Through an assay that made available the p53/MDM2 complex, hoiamide D was found to inhibit the activity of the interaction.

Potential therapeutic applications As partial agonists of VGSC, hoiamide A and B may be able to mimic activity-dependent control of neuronal development through the up-regulation of pathways that influence neuronal growth and plasticity. Hoiamide D is a molecule that may have applications as a precursor molecule for cancer therapies.

References

Illustrations

Worked examples

Example 1 — a first encounter with Hoiamides

Start with the simplest possible case. Write down what Hoiamides claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Hoiamides before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Hoiamides ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Hoiamides

In research: Hoiamides appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Hoiamides in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Hoiamides is common in secondary-school and first-year university syllabi. It links to neighbouring topics Polyketides, Thiazoles, so understanding it makes those chapters shorter.
In everyday life: Look for Hoiamides outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Hoiamides in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Hoiamides means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Hoiamides out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Hoiamides in simple terms?

The hoiamides are a class of small molecules recently characterized from isolations of secondary metabolites of cyanobacteria that feature a triheterocyclic system. Hoiamide A and B are cyclic while hoiamide C and D are linear.

Why does Hoiamides matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Hoiamides?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Hoiamides.