Sirtuin

Key takeaways

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

Reference excerpt

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast. Yeast Sir2 and some, but not all, sirtuins are protein deacetylases. Unlike other known protein deacetylases, which simply hydrolyze acetyl-lysine residues, the sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD+ hydrolysis. This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB and IV), which have a different protein fold and use Zn2+ as a cofactor.

Actions and species distribution Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, sir2 is the name of one of the sirtuin-type proteins (see table below). Mammals possess seven sirtuins (SIRT1–7) that occupy different subcellular compartments: SIRT1, SIRT6 and SIRT7 are predominantly in the nucleus, SIRT2 in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in the mitochondria.

History Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT. Interest in the metabolism of NAD+ heightened after the year 2000 discovery by Shin-ichiro Imai and coworkers in the Guarente laboratory that sirtuins are NAD+-dependent protein deacetylases .

Types

The first sirtuin was identified in yeast (a fungus) and named sir2. In more complex mammals, there are seven known enzymes that act in cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes (I-IV), depending on their amino acid sequence structure. Several gram-positive prokaryotes as well as the gram-negative hyperthermophilic bacterium Thermotoga maritima possess sirtuins that are intermediate in sequence between classes, and these are placed in the "undifferentiated" or "U" class. In addition, several gram-positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes, as well as several fungi carry macrodomain-linked sirtuins (termed "class M" sirtuins).

SIRT3, a mitochondrial protein deacetylase, plays a role in the regulation of multiple metabolic proteins like isocitrate dehydrogenase of the TCA cycle. It also plays a role in skeletal muscle as a metabolic adaptive response. Since glutamine is a source of α-ketoglutarate used to replenish the TCA cycle, SIRT4 is involved in glutamine metabolism.

Ageing Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1, led some scientists to speculate that resveratrol may extend lifespan, no clinical evidence for such an effect has been discovered, as of 2018.

Tissue fibrosis

A 2018 review indicated that SIRT levels are lower in tissues from people with scleroderma, and such reduced SIRT levels may increase risk of fibrosis through modulation of the TGF-β signaling pathway.

DNA repair in laboratory studies SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair. SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks. SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage. SIRT6 deficiency in mice leads to a degenerative aging-like phenotype. In addition, SIRT6 promotes the repair of DNA double-strand breaks. Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair. SIRT7 knockout mice display features of premature aging. SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining.

Inhibitors Certain sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site. It is an inhibitor in vitro of SIRT1, but can be a stimulator in cells.

Activators

See also Biological immortality Histone deacetylases or HDACs Trichostatin A

References

External links Sirtuins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

Illustrations

Worked examples

Example 1 — a first encounter with Sirtuin

Start with the simplest possible case. Write down what Sirtuin claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, 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 Sirtuin 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 Sirtuin 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 Sirtuin

In research: Sirtuin appears in biology 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 Sirtuin 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: Sirtuin is common in secondary-school and first-year university syllabi. It links to neighbouring topics Aging-related enzymes, Aging-related proteins, Enzymes, so understanding it makes those chapters shorter.
In everyday life: Look for Sirtuin 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 Sirtuin in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Sirtuin 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 Sirtuin out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Sirtuin in simple terms?

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life.

Why does Sirtuin matter?

Because it connects several biology 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 Sirtuin?

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 Sirtuin.