Abstract: Phenylalanine hydroxylase catalyzes the stereospecific hydroxylation o

Question

Abstract: Phenylalanine hydroxylase catalyzes the stereospecific hydroxylation ofh-phenylalanine, the committed step in the degradation of this aminolacid. We have solved the crystal structure of the ternary complex!(Fe(ID) BH-THA) of the catalytically active Fe(II) form of a truncatedlform (DN1-102/DC428 452) of human phenylalanine hydroxylase!(hPheOH), using the catalytically active reduced cofactor 6(R)-L-erythro- 5,6,7,8-tetrahydrobiopterin (BH.) and 3-(2-thienyl)-1-alanine (THA) as alsubstrate analogue. The analogue is bound with the thiophene ring stacking againstlthe imidazole group of His285 (average interplanar distance 3.8 angstroms) andlwith a network of hydrogen bonds and hydrophobic contacts. Binding ofithe analogue to the binary complex Fe(IT)-BH triggers structurallchanges throughout the entire molecule. The largest change occurs in the loop region comprising residues 131-155. This loop is refolded, bringing the hydroxyl oxygen atom of Tyr138 closer to the iron atom and into the active site. BH is displaced 2.6 angstroms in the direction of Glu286 and the iron atom, relative to the Fe(l)-BH.structure, thus changing its hydrogen bonding network. The active-site structure oflthe temary complex gives new insight into the substrate specificity of thelenzyme, notably the low affinity for i-tyrosine. Furthermore, the structurelhas implications both for the catalytic mechanism and the molecular basislfor the activation of the full-length tetrameric enzyme by its substrate. Thellarge conformational change, moving Tyrl38 from a surface position intolthe active site, may reflect a possible functional role for this residue. MacBook Pro

Explanation / Answer

L-phenylalanine catalysis of the stereospecific hydroxylation by phenylalanine hydroxylase, the dedicated step in this amino acid degradation. The catalytically active Fe(II) ternary complex (Fe(II)·BH4·THA) crystal structure human phenylalanine hydroxylase (hPheOH) form of a abbreviated form (DN1–102/DC428–452) , A substrate analogue taken as the catalytically active reduced cofactor BH4 as well as THA. The analogue is constrained with the thiophene ring piling against the His285 imidazole group (mean interplanar distance 3.8 angstroms) also with a hydrogen bonds also hydrophobic contacts networks. Restricting of the analogue with the binary complex Fe(II)·BH4 generate structural changes during the whole of the entire molecule. The largest change produces in the loop region consisting 131–155 residues. This loop is refolded, taking the Tyr138 hydroxyl oxygen atom adjacent to the iron atom also into the active site. In the route of Glu286 and the iron atom, BH4 is disturbed 2.6 angstroms, respective to the Fe(II)· Structure of BH4,hence altering its network of hydrogen bonding. The ternary complex  active-site structure provide new insight into the enzyme substrate specificity, especially the L-tyrosine low affinity. Moreover, the structure has association for the catalytic mechanism as well as the molecular basis for the full-length tetrameric enzyme activation by its substrate. The bigger conformational change,Tyr138 migrating from a surface position into the active site, may show available functional role for this residue.

Related Questions

Navigate

• Browse (All)
• Browse A
• Subjects

---

---

Integrity-first tutoring: explanations and feedback only — we do not complete graded work. Learn more.