science

Radical SAM enzymes

Radical SAM enzymes is a science topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Radical SAM enzymes rather than just read about it. In short: Radical SAM enzymes belong to a superfamily of enzymes that use an iron-sulfur cluster (4Fe-4S) to reductively cleave S-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′-deoxyadenosyl radical (5'-dAdo), as a critical intermediate. These enzymes utilize this radical intermediate to perform diverse transformations, often to functionalize unactivated C-H bonds.

Key takeaways

Radical SAM enzymes belongs to science; place it in that map before memorising details.
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Connect Radical SAM enzymes to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Radical SAM enzymes from memory before moving on to harder problems.

Reference excerpt

Radical SAM enzymes belong to a superfamily of enzymes that use an iron-sulfur cluster (4Fe-4S) to reductively cleave S-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′-deoxyadenosyl radical (5'-dAdo), as a critical intermediate. These enzymes utilize this radical intermediate to perform diverse transformations, often to functionalize unactivated C-H bonds. Radical SAM enzymes are involved in cofactor biosynthesis, enzyme activation, peptide modification, post-transcriptional and post-translational modifications, metalloprotein cluster formation, tRNA modification, lipid metabolism, biosynthesis of antibiotics and natural products etc. The vast majority of known radical SAM enzymes belong to the radical SAM superfamily, and have a cysteine-rich motif that matches or resembles CxxxCxxC. Radical SAM enzymes comprise the largest superfamily of metal-containing enzymes.

History and mechanism As of 2001, 645 unique radical SAM enzymes have been identified from 126 species in all three domains of life. According to the EFI and SFLD databases, more than 220,000 radical SAM enzymes are predicted to be involved in 85 types of biochemical transformations. The mechanism for these reactions entail transfer of a methyl or adenosyl group from sulfur to iron. The resulting organoiron complex subsequently releases the organic radical. The latter step is reminiscent of the behavior of adenosyl and methyl cobalamins.

Nomenclature All enzymes including radical SAM enzymes follow an easy guideline for systematic naming. Systematic naming of enzymes allows a uniform naming process that is recognized by all scientists to understand corresponding function. The first word of the enzyme name often shows the substrate of the enzyme. The position of the reaction on the substrate will also be in the beginning portion of the name. Lastly, the class of the enzyme will be described in the other half of the name which will end in suffix -ase. The class of an enzyme will describe what the enzyme is doing or changing on the substrate. For example, a ligase combines two molecules to form a new bond.

Reaction classification Representative enzymes will be mentioned for each class. Radical SAM enzymes and their mechanisms known before 2008 are summarized by Frey et al. Since 2015, additional review articles on radical SAM enzymes are available, including:

Advances in Radical SAM Enzymology: New Structures and Mechanisms: Radical S-Adenosylmethionine Enzymes: Radical S-Adenosylmethionine (SAM) Enzymes in Cofactor Biosynthesis: A Treasure Trove of Complex Organic Radical Rearrangement Reactions: Molecular architectures and functions of radical enzymes and their (re)activating proteins: Radical SAM enzymes in RiPP biosynthesis. Radical SAM enzymes with a vitamin B12 (cobalamin)-binding domain.

Carbon methylation Radical SAM methylases/methyltransferases are one of the largest yet diverse subgroups and are capable of methylating a broad range of unreactive carbon and phosphorus centers. These enzymes are divided into three classes (Class A, B and C) with representative methylation mechanisms. The shared characteristic is the usage of SAM, split into two distinct roles: one as a source of a methyl group donor, and the second as a source of 5'-dAdo radical. Another class has been proposed (class D) but proved to be wrongly assigned.

Class A sub-family Class A enzymes methylate specific adenosine residues on rRNA and/or tRNA. In other words, they are RNA base-modifying radical SAM enzymes. The most mechanistically well-characterized are enzymes RlmN and Cfr. Both enzymes methylates substrate by adding a methylene fragment originating from SAM molecule. Therefore, RlmN and Cfr are considered methyl synthases instead of methyltransferases.

Class B sub-family Class B enzymes are the largest and most versatile which can methylate a wide range of carbon and phosphorus centers. These enzymes require a cobalamin (vitamin B12) cofactor as an intermediate methyl group carrier to transfer a methyl group from SAM to substrate. One well-investigated representative enzyme is TsrM which involves in tryptophan methylation in thiostrepton biosynthesis.

Class C sub-family Class C enzymes are reported to play roles in biosynthesis of complex natural products and secondary metabolites. These enzymes methylate heteroaromatic substrates and are cobalamin-independent. These enzymes contain both the radical SAM motif and exhibit striking sequence similarity to coproporhyrinogen III oxidase (HemN), a radical SAM enzyme involved in heme biosynthesis Detailed mechanistic investigations on two class C radical SAM methylases have been reported: TbtI is involved in the biosynthesis of potent thiopeptide antibiotic thiomuracin. Jaw5 is suggested to be responsible for cyclopropane modifications.

Methylthiolation of tRNAs Methylthiotransferases belong to a subset of radical SAM enzymes that contain two [4Fe-4S]+ clusters and one radical SAM domain. Methylthiotransferases play a major role in catalyzing methylthiolation on tRNA nucleotides or anticodons through a redox mechanism. Thiolation modification is believed to maintain translational efficiency and fidelity. MiaB and RimO are both well-characterized and bacterial prototypes for tRNA-modifying methylthiotransferases

MiaB introduces a methylthio group to the isopentenylated A37 derivatives in the tRNA of S. Typhimurium and E. coli by utilizing one SAM molecule to generate 5'-dAdo radical to activate the substrate and a second SAM to donate a sulfur atom to the substrate. RimO is responsible for post-translational modification of Asp88 of the ribosomal protein S12 in E. coli. The crystal structure sheds light on the mechanistic action of RimO. The enzyme catalyzes pentasulfide bridge formation linking two Fe-S clusters to allow for sulfur insertion to the substrate. eMtaB is the designated methylthiotransferase in eukaryotic and archaeal cells. eMtaB catalyzes the methylthiolation of tRNA at position 37 on N6-threonylcarbamoyladenosine. A bacterial homologue of eMtaB, YqeV has been reported and suggested to function similarly to MiaB and RimO.

Sulfur insertion into unreactive C-H bonds Sulfurtransferases are a small subset of radical SAM enzymes. Two well-known examples are BioB and LipA which are independently responsible for biotin synthesis and lipoic acid metabolism, respectively.

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Illustrations

Worked examples

Example 1 — a first encounter with Radical SAM enzymes

Start with the simplest possible case. Write down what Radical SAM enzymes 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 Radical SAM enzymes 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 Radical SAM enzymes 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 Radical SAM enzymes

In research: Radical SAM enzymes 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 Radical SAM enzymes 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: Radical SAM enzymes is common in secondary-school and first-year university syllabi. It links to neighbouring topics Enzymes, so understanding it makes those chapters shorter.
In everyday life: Look for Radical SAM enzymes 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.

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How to study Radical SAM enzymes in 20 minutes

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Frequently asked questions

What is Radical SAM enzymes in simple terms?

Why does Radical SAM enzymes 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 Radical SAM enzymes?

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 Radical SAM enzymes.