Substituted 2-Azabicyclo[2.1.1]hexanes as Constrained Proline Analogues:  Implications for Collagen Stability.

Jenkins, Cara L.; Lin, Guoliang; Duo, Jingqi; Rapolu, Deepa; Guzei, Ilia A.; Raines, Ronald T.; Krow, Grant R.

doi:10.1021/jo052444p

Cited by 6 publications

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“…[56][57][58] Pro in the X AA prefers up puckering, whereas the Hyp at the Y AA prefers down puckering. The average puckering of Pro and Hyp for different model collagens is listed in Table 1 with the standard deviation.…”

Section: Resultsmentioning

confidence: 99%

Role of Length-Dependent Stability of Collagen-like Peptides

et al. 2008

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Understanding the structure, folding, and stability of collagen is complex because of its length and variations in the amino acid (AA) sequence composition. It is well known that the basic constituent of the collagen helix is the triplet repeating sequence of the form Gly-X(AA)-Y(AA). On the basis of previous models and with the frequency of occurrence of the triplets, the ((Gly-Pro-Hyp)n)3 (where n is the number of triplets) sequence replicate has been chosen as the model for the most stable form of the collagen-like sequence. With a view to understand the role of sequence length (or the number of triplets) on the stability of collagen, molecular dynamics simulations have been carried out by varying the number of triplet units on the model collagen-like peptides. The results reveal that five triplets are required to form the stable triple helix. Further analysis shows that the intermolecular structural rigidity of the imino acid residues, hydrogen bonding, and water structure around the three chains of the triple helix play the dominant roles on its structure, folding, and stabilization.

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Section: Resultsmentioning

confidence: 99%

Role of Length-Dependent Stability of Collagen-like Peptides

et al. 2008

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“…In essence, this analog has two C-4 carbons and thus always displays both ring puckers (72). Mtp has a trans / cis ratio that is between that of Pro and flp (44). We find that P4H does not hydroxylate either C-4 carbon of Mtp, and that Mtp does not inhibit P4H activity.…”

Section: Discussionmentioning

confidence: 99%

“…Boc-D,L-MtpOH was prepared by the route shown in Scheme 1, which is less costly and more convenient than those described previously (44, 45). Briefly, carbamate 1 was prepared as in ref.…”

Section: Methodsmentioning

confidence: 99%

“…44 and 47, 3-CH 2 OH ( 2 ) (600 mg, 2.813 mmol) was dissolved in a solution of CH 2 Cl 2 (14 mL), TEMPO (27 mg), saturated NaHCO 3 (aq) (11 mL), KBr (54 mg), and Bu 4 NCl (67 mg). This solution was cooled to 0 °C, and a solution of NaOCl (14 mmol), saturated NaHCO 3 (aq) (6 mL), and brine (12 mL) was added dropwise over 45 min.…”

Section: Methodsmentioning

confidence: 99%

“…The aqueous layers were combined, and washed with CH 2 Cl 2 (2 × 25 mL), acidified with dilute HCl solution until the pH was <3, and then extracted with ethyl acetate (5 × 200 mL). The combined organic extracts were dried over Na 2 SO 4 (s), and the solvent was removed to furnish Boc-D,L-MtpOH (524 mg, 82%) as off-white solid of sufficient purity (44, 45, 47). …”

Section: Methodsmentioning

confidence: 99%

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Conformational Preferences of Substrates for Human Prolyl 4-Hydroxylase

et al. 2008

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Prolyl 4-hydroxylase (P4H) catalyzes the post-translational hydroxylation of (2S)-proline (Pro) residues in procollagen strands. The resulting (2S,4R)-4-hydroxyproline (Hyp) residues are essential for the folding, secretion, and stability of the collagen triple helix. Even though its product (Hyp) differs from its substrate (Pro) by only a single oxygen atom, no product inhibition has been observed for P4H. Here, we examine the basis for the binding and turnover of substrates by human P4H. Synthetic peptides containing (2S,4R)-4-fluoroproline (Flp), (2S,4S)-4-fluoroproline (flp), (2S)-4-ketoproline (Kep), (2S)-4-thiaproline (Thp), and 3,5-methanoproline (Mtp) were evaluated as substrates for P4H. Peptides containing Pro, flp, and Thp were found to be excellent substrates for P4H, forming Hyp, Kep, and (2S,4R)-thiaoxoproline, respectively. Thus, P4H is tolerant to some substitutions on C-4 of the the pyrrolidine ring. In contrast, peptides containing Flp, Kep, or Mtp did not even bind to the active site of P4H. Each proline analog that does bind to P4H is also a substrate, indicating that discrimination occurs at the level of binding rather than turnover. As the iron(IV)-oxo species that forms in the active site of P4H is highly reactive, P4H has an imperative for forming a snug complex with its substrate, and appears to do so. Most notably, those proline analogs with a greater preference for a C γ -endo pucker and cis peptide bond were the ones recognized by P4H. As Hyp has a strong preference for C γ -exo pucker and trans peptide bond, P4H appears to discriminate against the conformation of proline residues in a manner that diminishes product inhibition during collagen biosynthesis.Collagens are the major structural proteins in the extracellular matrix. All collagens are comprised of three polypeptide strands that coil together into a right-handed triple helix. Each strand contains a repeating three amino-acid sequence in which every third residue is a glycine (Gly 1 ): Xaa-Yaa-Gly. The Xaa position is often (2S)-proline (Pro), and the Yaa position is often (2S,4R)-4-hydroxyproline (Hyp) (1). Hyp is produced by the action of prolyl 4-hydroxylase (P4H; EC 1.14.11.2). This post-translational modification is the most prevalent † This work was supported by Grants AR044276 (NIH to R.T.R) and CHE 0515635 (NSF to G.R.K.). K.L.G. was supported by ChemistryBiology Interface Training Grant T32 BM008505 (NIH). MALDI-MS experiments were performed at the University of WisconsinMadison Biophysics Instrumentation Facility, which was established with Grants BIR-9512577 (NSF) and RR13790 (NIH).*To whom correspondence should be addressed: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544. Telephone: 608-262-8588. Fax: 608-262-3453. rtraines@wisc.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2010 January 22. in the kingdom Animalia, where Hyp is more common than seven of the "common" aminoacid residues: Cys, Gln, His, Met, P...

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