Introduction
The two protein subunits possess dense regions of
Main points:
- introduce general characteristics of protein (location within cell, substrate activity, relation to cysteamine)
- A small paragraph on its discovery
- The broad impact of the protein (what happens if it loses function?)
Overall Structure
- 506 total residues, 87 missing
- Two chains, each with many alpha helices and beta sheets
-
43 missing residues: 8-20, 484-513
- Chain B
44 missing residues: 8-20, 484-513
Ligands and non-standard residues
- 2 RRV
- 2 PEG
- 8 NAG
Binding Interactions
4CYG is a key protein that is involved in the breakdown of pantetheine to panthothenic acid and cysteamine. These proteins are associated with many metabolic diseases like type 2 diabetes. Understanding the binding interaction would give insight into treating these diseases more effectively. 4CYG has three (Glu79, Lys178 and Cys211) that represents the active site of the enzyme. The purple amino acids represent the three amino acids directly involved in the binding interactions. The active site is located in the center of the enzyme in between the two sub-units. It was discovered that Glu79 and Lys178 were responsible for orienting and activating Cys211 to catalyze the reaction. The substrate forms a covalent bond with Cys211 producing the transition state.[1]
In addition, the two residues are essential for enzymatic function too. The purple regions are polar whereas the grey regions are hydrophobic. The two black amino acids represent GLU249 and GLU439. The two glutamic acid residues are both located in hydrophobic regions 4 Angstroms away. Although this is energetically unfavorable to have a polar amino acid in a nonpolar region, these two amino acids help maintain the structure between the two sub-units for proper binding interactions to occur.[1]
Additional Features
The biological importance of pantetheinase is found in the products cysteamine and vitamin B5, formed from the hydrolysis reaction shown below. Cysteamine and vitamin B5 are key components in the synthesis of other necessary biomolecules such as acetylcholine and coenzyme A.
Inhibition
The importance of pantetheinase stems from the vitality of the components of the reaction it catalyzes. It is for this reason that pantetheinase has been a promising point of research in the field of medicine. Pantetheine analogues known as pantothenamides have been shown to act as effective antibiotics that protect the body from bacterial intruders. The similarity of these analogues to pantetheine allows for the active sites of pantetheinase to catalyze their breakdown through hydrolysis. The administration of RR6 in the presence of pantetheinase and other antibiotic pantothenamides revealed that RR6 acts as a competitive inhibitor with great affinity for the active sites on pantetheinase, thus preserving desired concentrations of the pantothenamides with antibiotic characteristics.
Absence
Vitamin B5 is the recycled product of the hydrolysis of pantetheine and is a major substrate in the formation of coenzyme A (CoA). Without pantetheinase, the hydrolysis of pantetheine would occur at a significantly slower rate and would therefore produce vitamin B5 and cysteamine at a slower rate. Lower concentrations of Vitamin B5 would result in inadequate prodution of CoA and therefore inadequate production of acetylcholine. Acetylcholine is a neurotransmitter that is needed for proper brain function so an absence of pantetheinase could eventually lead to neurological complications.
Cysteamine is important in the regulation of cystine levels in lysosomes. A lack of cysteamine due to the absence of pantetheinase would lead to a build up of lysosomal cystine, a disease known as cystinosis.
Quiz Question 1
- Additional research needed to formulate question (may potentially pertain to structure-substrate interaction)
See Also
Credits
Introduction - Patrick Tonne
Overall Structure - Luke Schnitzler
Drug Binding Site - Owen O'Connor
Additional Features - Nick Sant
Quiz Question 1 - Tyler Russell
References
- ↑ Boersma YL, Newman J, Adams TE, Cowieson N, Krippner G, Bozaoglu K, Peat TS. The structure of vanin 1: a key enzyme linking metabolic disease and inflammation. Acta Crystallogr D Biol Crystallogr. 2014 Dec 1;70(Pt 12):3320-9. doi:, 10.1107/S1399004714022767. Epub 2014 Nov 28. PMID:25478849 doi:http://dx.doi.org/10.1107/S1399004714022767
