Disease relevance of Leu-Leu

• When domain I of PE66 is replaced by a segment comprising the first two domains of CD4, the resulting chimeric protein is hydrolyzed at the same Leu-Leu bond by HIV-1 protease [1].
• The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38) [2].
• For P757L, patients with the Leu/Leu genotype showed a reduced risk of colorectal cancer (adjusted OR = 0.398, 95% CI 0.183-0.866) when the Pro/Leu and Pro/Pro genotypes were combined and used as the reference [3].
• The crystallographic structure of NAD-A(4)-GAPDH highlights that four residues, Thr33, Ala40, Ser188, and Ala187 (Leu, Leu, Pro, and Leu respectively, in glycolytic Bacillus stearothermophilus GAPDH sequence) are of primary importance for the dual cofactor specificity of photosynthetic GAPDH [4].
• RESULTS: We confirmed the increased susceptibility for diabetic retinopathy for the Leu/Leu genotype (odds ratio (OR) 3.34 (confidence interval (CI) 1.95, 5.75), P < 0.0001) [5].

Psychiatry related information on Leu-Leu

• RESULTS: Subjects carrying Leu/Leu were susceptible to both ischemic stroke (odds ratio [OR]=1.63; P<0.05) and vascular dementia (OR=1.88; P<0.01) [6].

High impact information on Leu-Leu

• In addition to all previously identified products of the egg-laying hormone (ELH) gene, other peptides are formed from proteolytic hydrolysis of Leu-Leu residues within ELH and acidic peptide (AP) [7].
• The distribution of genotypes was different in cases (63. 2% Val/Val; 30.9% Val/Leu; 5.9% Leu/Leu) compared with controls (49. 8% Val/Val; 42.8% Val/Leu; 7.4% Leu/Leu; P <.001) [8].
• Our findings suggest that in cell extracts the Leu-Leu motif of A' is required for reconstitution with U2 snRNPs and perhaps with other components involved in splicing through protein-protein interactions [9].
• Replacement of Leu-Leu in ortho-aminobenzoyl (Abz)-Thr-Leu-Leu-Ser-Ala-Leu-Gln-N-(2, 4-dinitrophenyl)ethylenediamine (EDDnp) by Pro-Phe in Abz-Thr-Pro-Phe-Ser-Ala-Leu-Gln-EDDnp produced the most sensitive substrate of cathepsin G ever reported [10].
• Porcine pepsin proteolysis of the hexapeptide Leu-Ser-p-nitro-Phe-Nle-Ala-Leu-OMe (where OMe = methoxy and Nle = norleucine) in the presence of dipeptide Leu-Leu synthesizes a new hexapeptide Leu-Ser-p-nitro-Phe-Leu-Leu [11].

Chemical compound and disease context of Leu-Leu

• HIV-1 protease catalyzes cleavage of this substrate at the same Leu-Leu bond as does porcine renin, resulting in the formation of authentic angiotensin-I [12].

Biological context of Leu-Leu

• However, with Leu-Leu as substrate normal Michaelis-Menten kinetics were obeyed [13].
• In the case of the hybridomas reactive to the nonstructural protein, sequence analysis showed that they all expressed V alpha 4J alpha 32 chains associated with the same junctional amino acids (Leu-Leu) that were encoded by five different nucleotide sequences, indicating a strong selection for T-cell receptor usage [14].
• Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a 2-fold risk increase for NHL (OR=2.2, 95% CI=1.1-4.4) (referent=Ser/Ser and Ser/Leu) [15].
• Membrane ion-transport studies have shown that the norborneno cyclic peptides 4b and 7b containing Leu-Leu or Val-Val pendants symmetrically placed on the exterior of the ring show high efficiency and selectivity in the transport of specifically monovalent cations [16].
• RESULTS: Allele frequencies were not different from term and VLBW infants (Val/Val, 53.1% and 57.8%; Val/Leu, 38.8% and 37.6%; Leu/Leu, 8.0% and 4.5%, respectively) [17].

Anatomical context of Leu-Leu

• A Leu-Leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts [18].
• Cleavage near and between Leu-Leu residues is observed in the abdominal and buccal ganglia homogenates, confirming the presence of an unidentified peptidase [19].
• The purpose of the present study was to investigate the utilisation of vascularly administered leucyl-leucine (Leu-Leu), alanyl-glutamine (Ala-Gln) and glycyl-glutamine (Gly-Gln) by the isolated vascularly perfused rat small intestine [20].
• CONCLUSIONS: Because prevalence of homozygous Leu genotype was significantly higher in controls, we conclude that the Leu/Leu genotype is associated with a protective effect against retinal artery occlusion [21].

Associations of Leu-Leu with other chemical compounds

• Using the random effects methods, protective effects were seen with the Leu/Val genotype alone (OR 0.79, 95% CI 0.68-0.93) and with Leu/Val and Leu/Leu genotypes combined (OR 0.79, 95% CI 0.66-0.93) [22].
• Products resulting from cleavage at Leu-Leu sites are observed and are produced in larger amounts in acidic and neutral pH ranges, and cleavage is inhibited by the addition of EDTA, suggesting a metal is required for activity [19].
• However, when jimpy brain proteolipids were subjected to N-terminal sequencing, Gly, Leu, Leu, Gly the first four amino acids of PLP were detected [23].
• The Leu/Leu (LL), Leu/Met (LM) and Met/Met (MM) genotypes at position 55 were noted in 131 (43.2%), 128 (42.2%) and 44 (14.5%) subjects; the Gln/Gln (QQ), Gln/Arg (QR) and Arg/Arg (RR) genotypes at codon 192 occurred in 167 (55.1%), 118 (38.9%) and 18 (5.9%) individuals, respectively [24].

Gene context of Leu-Leu

• PON1 Leu/Leu increases the risk for retinopathy and PON2 Ser/Ser increases the risk for microalbuminuria [5].
• The enzymes showed homogeneity, appearing as a single band on SDS/PAGE, and the M(r) values of the subunits were 56,000 and 57,000 for Leu-Leu and Ala-Gly dipeptidase respectively [25].
• RESULTS: The distribution of genotypes was Leu-Leu (41.8%), Leu-Pro (50.3%), and Pro-Pro (7.9%) for subjects with COPD, which was significantly different from the control subjects (blood donors: Leu-Leu (29.3%), Leu-Pro (52.1%) and Pro-Pro (18.6%), p=0.006; resistant smokers: Leu-Leu (28.9%), Leu-Pro (51.3%) and Pro-Pro (19.7%), p=0.02) [26].
• The risk of all-cause and cardiovascular mortality was not increased in elderly subjects with the paraoxonase Leu/Leu (RR, 1.1 [95% CI, 0.9-1.5] and 1.3 [95% CI, 0.8-2.0], respectively) or the Arg/Arg genotype (RR, 0. 9 [95% CI, 0.7-1.2] and 0.7 [95% CI, 0.4-1.3], respectively) [27].
• Km values of 0.70 and 0.44 mM were determined for the dipeptidase on Leu-Leu and the aminopeptidase on Leu-p-nitroanilide, respectively [28].

Analytical, diagnostic and therapeutic context of Leu-Leu

• In addition, fractions from an HPLC separation of buccal ganglia homogenates also produce cleavages at Leu-Leu residues [19].
• To further investigate this unusual event, native and non-native synthetic peptides containing Leu-Leu residues are incubated with homogenates of Aplysia californica ganglia and the resulting products monitored with MALDI MS [19].
• The presence of built-in handles (as protected COOH groups) permits the attachment of a variety of subunits as shown here with the ligation of Leu-Leu, Val-Val, or Aib-Aib pendants in 4b, 7b, and 13b, respectively [16].
• Native-polyacrylamide gel electrophoresis (PAGE) and gel filtration column chromatographic analysis showed that the molecular size of Pro-9/Leu/Leu is roughly half of that of BLMA, suggesting that the mutant protein cannot form dimeric structure [29].
• Furthermore, Far-UV circular dichroism (CD) spectrum of Pro-9/Leu/Leu was quite different from that of BLMA and similar to the spectra obtained from unordered proteins [Venyaminov, S.Y. and Vassilenko, K.S. (1994) Anal. Biochem. 222, 176184], suggesting that the secondary structure of Pro-9/Leu/Leu is disrupted [29].

References