engineering

Phosphoribosylamine—glycine ligase

Phosphoribosylamine—glycine ligase is a engineering 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 Phosphoribosylamine—glycine ligase rather than just read about it. In short: Phosphoribosylamine—glycine ligase, also known as glycinamide ribonucleotide synthetase (GARS), (EC 6.3.4.13) is an enzyme that catalyzes the chemical reaction ATP + 5-phospho-D-ribosylamine + glycine ⇌ {\displaystyle \rightleftharpoons } ADP + phosphate + N1-(5-phospho-D-ribosyl)glycinamide which is the second step in purine biosynthesis. The 3 substrates of this enzyme are ATP, 5-phospho-D-ribosylamine, and glycin…

Key takeaways

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Reference excerpt

Phosphoribosylamine—glycine ligase, also known as glycinamide ribonucleotide synthetase (GARS), (EC 6.3.4.13) is an enzyme that catalyzes the chemical reaction

ATP + 5-phospho-D-ribosylamine + glycine ⇌ {\displaystyle \rightleftharpoons } ADP + phosphate + N1-(5-phospho-D-ribosyl)glycinamide which is the second step in purine biosynthesis. The 3 substrates of this enzyme are ATP, 5-phospho-D-ribosylamine, and glycine, whereas its 3 products are ADP, phosphate, and N1-(5-phospho-D-ribosyl)glycinamide. This enzyme belongs to the family of ligases, specifically those forming generic carbon-nitrogen bonds. In bacteria, GARS is a monofunctional enzyme (encoded by the purD gene). The purD genes often contain PurD RNA motif in their 5' UTR. In yeast, GARS is part of a bifunctional enzyme (encoded by the ADE5/7 gene) in conjunction with phosphoribosylformylglycinamidine cyclo-ligase (AIRS). In higher eukaryotes, including humans, GARS is part of a trifunctional enzyme in conjunction with AIRS and with phosphoribosylglycinamide formyltransferase (GART), forming GARS-AIRS-GART.

Nomenclature The systematic name of this enzyme class is 5-phospho-D-ribosylamine:glycine ligase (ADP-forming). Other names in common use include:

phosphoribosylglycinamide synthetase glycinamide ribonucleotide synthetase phosphoribosylglycineamide synthetase glycineamide ribonucleotide synthetase 2-amino-N-ribosylacetamide 5'-phosphate kinosynthase 5'-phosphoribosylglycinamide synthetase GAR synthetase

Mechanism GARS operates via an ordered, sequential mechanism. 5-phospho-D-ribosylamine (PRA) binds first, then ATP, and finally glycine. Phosphate is released first, followed by ADP and GAR. The oxygen in the ribose ring of PRA is important in substrate binding, likely due to favorable energetics from hydrogen bonding and the ring conformation it confers. In addition, the phosphate group of GAR has been implicated in GARS substrate recognition. The reaction starts with the oxygen of glycine acting as a nucleophile to attack the γ-phosphorus of ATP. Then, the nitrogen of PRA attacks the carbonyl carbon in the intermediate, and phosphate leaves, forming GAR.

Structural studies As of late 2007, 3 structures have been solved for this class of enzymes, with PDB accession codes PDB: 1GSO, PDB: 1VKZ, and PDB: 2QK4. The overall structure of the enzyme, based on crystallization from E. coli, consists of 16 alpha helices which connect to 20 beta strands by turns and loops. There are four main domains: N, A, B, and C. Each domain has a central beta sheet with an alpha helix on at least one side. The N, A, and C domains are clustered together, while the B domain is slightly separated from the others and connected to them by two hinge regions. The active site is between the NAC group and the B domain. The A and B domains appear to facilitate ATP binding, while the N and C domains confer substrate specificity. The N domain is very similar to that of glycinamide ribonucleotide transformylase. Although the orientation of the B domains varies, the structure of GARS is very similar across organisms. Furthermore, the gene has been sequenced in many organisms, and E. coli shows between 41 and 52% identity with the GARS sequences of B. subtilis, S. cerevisiae, D. melanogaster, and D. pseudobscura. Human GARS-AIRS-GART has been shown to be most similar to that of mice, chimpanzees, and cows. Among the amino acids that are identical in B. subtilis, S. cerevisiae, D. melanogaster, and D. pseudobscura, almost a third are glycine and proline, which suggests that they play an important role in proper folding of the protein. In addition to similar structure across species, GARS as a whole has a very similar structure to D-alanine:D-alanine ligase, biotin carboxylase, and glutathione synthetase. All of these enzymes have an ATP binding domain classified as ATP-grasp domains.

Disease relevance In humans, the gene that codes for GARS-AIRS-GART is on chromosome 21, and individuals with Down syndrome have higher purine levels, which has been correlated with intellectual disability. Thus, studies have been conducted to investigate its involvement in Down Syndrome. It has been found that GARS is expressed for longer in individuals with Down Syndrome than in unaffected individuals. In unaffected individuals, GARS is highly expressed in the cerebellum before birth but is barely expressed by three weeks after birth. In individuals with Down Syndrome, GARS expression continues until at least seven weeks after birth. This suggests that GARS may be a main contributor to the development of Down Syndrome. However, so far no mutations to GARS have been identified that could change its function and cause Down Syndrome related intellectual disability.

References

Illustrations

Worked examples

Example 1 — a first encounter with Phosphoribosylamine—glycine ligase

Start with the simplest possible case. Write down what Phosphoribosylamine—glycine ligase claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In engineering, 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 Phosphoribosylamine—glycine ligase 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 Phosphoribosylamine—glycine ligase 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 Phosphoribosylamine—glycine ligase

In research: Phosphoribosylamine—glycine ligase appears in engineering 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 Phosphoribosylamine—glycine ligase 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: Phosphoribosylamine—glycine ligase is common in secondary-school and first-year university syllabi. It links to neighbouring topics EC 6.3.4, Enzymes of known structure, so understanding it makes those chapters shorter.
In everyday life: Look for Phosphoribosylamine—glycine ligase 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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Frequently asked questions

What is Phosphoribosylamine—glycine ligase in simple terms?

Phosphoribosylamine—glycine ligase, also known as glycinamide ribonucleotide synthetase (GARS), (EC 6.3.4.13) is an enzyme that catalyzes the chemical reaction ATP + 5-phospho-D-ribosylamine + glycine ⇌ {\displaystyle \rightleftharpoons } ADP + phosphate + N1-(5-phospho-D-ribosyl)glycinamide which…

Why does Phosphoribosylamine—glycine ligase matter?

Because it connects several engineering 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 Phosphoribosylamine—glycine ligase?

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 Phosphoribosylamine—glycine ligase.