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Biology · CER Practice · Module 4 · Protein Synthesis · DE Unit 5

The Gila Monster's Glycine: One Amino Acid That Keeps a Signal Alive

Biology #19 SOL BIO.2d, BIO.2c, BIO.5e · one sheet, front and back

The Gila monster lives in the deserts of Arizona and northern Mexico and spends most of its life underground. It can live on three or four big meals a year, raiding nests for eggs and young birds, and can swallow a third of its body weight at once. Its bite carries venom from glands in its lower jaw. In 1992, Dr. John Eng's lab at the VA Medical Center in the Bronx pulled a chain of 39 amino acids out of that venom and named it exendin-4.

The same lock on a beta cell

After you eat, cells lining your gut release a hormone called GLP-1, a chain of 30 or 31 amino acids. It travels through the blood to beta cells in the pancreas and binds a receptor on their surface. When blood glucose is high, that signal tells the cells to release more insulin. Exendin-4 matches GLP-1 at 16 of its first 30 positions. The sequence folds into a similar shape, and the shape fits the same receptor on human beta cells. The lizard makes its own GLP-1 from a separate gene; the exendin-4 gene is switched on only in its venom glands.

Glycine at position 2 jams the scissors

Your own GLP-1 lasts only a minute or two. The blood carries an enzyme called DPP-4 that works like scissors. Its active site grips the first two amino acids of a chain and snips them off, and it does this fast when the second amino acid is alanine. GLP-1 has alanine there. Once its first two amino acids are gone, GLP-1 no longer switches on the receptor. Exendin-4 has glycine in that spot, and DPP-4 barely cuts it. Exendin-4 stays whole until the kidneys filter it out of the blood, and its half-life stretches to about 2.4 hours. In the genetic code, the gap between those two amino acids can be a single base: the codon GCU codes for alanine and GGU codes for glycine.

Chemists copied it, then redesigned it

No one milks lizards for medicine. Chemists build an exact copy of exendin-4, called exenatide, and in 2005 the FDA approved it as Byetta for type 2 diabetes. A later team started from human GLP-1 and made two key changes. At position 2 they placed Aib, an amino acid that is not one of the 20 that ribosomes use, so no codon codes for it and no cell could put it there. They also attached a fatty acid that makes the molecule cling to albumin, a large blood protein too big for the kidneys to filter. The result, semaglutide, was approved as Ozempic in 2017. Its half-life is about one week. All three molecules fit the same receptor and carry the same message; they differ in how long the blood keeps them.

Table 1. Three molecules that switch on the same human receptor. Half-life is the time for half of the molecule to be cleared from the blood.
FeatureGLP-1 (yours)Exendin-4 (lizard)Semaglutide
Made bycells lining the gutvenom glands; medicine is a lab copychemists, from human GLP-1
Length30–31 amino acids39 amino acids31 amino acids
Amino acid at position 2alanineglycineAib (no codon)
Matches GLP-1, first 30 positions30 of 3016 of 3028 of 30, plus a fatty acid
Cut by DPP-4?yes, within minutesbarelybarely
Main way it leaves the bloodDPP-4 cuts itkidneys filter itheld on albumin; cleared slowly
Half-life in the bloodabout 1–2 minutesabout 2.4 hoursabout 1 week
Hormone
A chemical messenger made in one place that travels in the blood to act elsewhere.
Receptor
A protein on a cell's surface shaped to fit one kind of signal molecule.
Insulin
A hormone from the pancreas that helps body cells take glucose out of the blood.
Active site
The pocket of an enzyme where its substrate fits and the reaction happens.
Codon
Three bases in mRNA that code for one amino acid.
Half-life
The time it takes for half of a substance to be removed or broken down.

Sources: Eng and others, J. Biol. Chem. 1992; Chen and Drucker, J. Biol. Chem. 1997; Göke and others, J. Biol. Chem. 1993; Mentlein and others, Eur. J. Biochem. 1993; Deacon and others, Diabetes 1995; Müller and others, Molecular Metabolism 2019; Lau and others, J. Med. Chem. 2015; FDA prescribing information for Byetta and Ozempic; Smithsonian's National Zoo; UniProt P01275 and P26349. See the three molecules move in Bio Tool #15, The Signal Patch. A biology reading, not medical advice. SOL codes are a judgment call.

Practice: Claim, Evidence, Reasoning

Claim: one sentence that answers the question and could be shown wrong. Evidence: a number, a row of Table 1, or a line from the reading. Reasoning: the principle that ties them together.

  1. Claim only

    Exendin-4 and your own GLP-1 fit the same receptor. Write a claim that explains why exendin-4 stays in the blood so much longer.

    Claim
  2. Full CER · from the data

    Using Table 1, decide whether the amino acid at position 2 affects how long a molecule lasts in the blood. Your evidence must compare two columns and quote at least one half-life.

    Claim
    Evidence
    Reasoning
  3. Full CER · from the reading

    A classmate says, “Exendin-4 comes from a lizard, so it must work on a lizard receptor, not on ours.” Decide whether the reading supports that.

    Claim
    Evidence
    Reasoning
  4. Mastery · new situation

    Your gut releases a second hormone after a meal, called GIP. Its chain begins tyrosine, alanine, glutamic acid, glycine. DPP-4 is in the same blood. Predict whether GIP lasts minutes or hours once it is released.

    Claim
    Evidence
    Reasoning
    What would change my mind
  5. Advanced Biology and DE Biology

    A student says semaglutide lasts a week because Aib at position 2 keeps DPP-4 from cutting it. Use the exendin-4 column to decide whether that one change explains a week, or whether a second change is needed.

    Claim
    Reasoning

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