Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of north-west European origin, and a person from China1–4. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1. The genome of AK1 was determined by an exacting, combined approach that included whole-genome shotgun sequencing (27.8× coverage), targeted bacterial artificial chromosome sequencing, and high-resolution comparative genomic hybridization using custom microarrays featuring more than 24 million probes. Alignment to the NCBI reference, a composite of several ethnic clades5,6, disclosed nearly 3.45 million single nucleotide polymorphisms (SNPs), including 10,162 non-synonymous SNPs, and 170,202 deletion or insertion polymorphisms (indels). SNP and indel densities were strongly correlated genome-wide. Applying very conservative criteria yielded highly reliable copy number variants for clinical considerations. Potential medical phenotypes were annotated for non-synonymous SNPs, coding domain indels, and structural variants. The integration of several human whole-genome sequences derived from several ethnic groups will assist in understanding genetic ancestry, migration patterns and population bottlenecks.

The biosynthesis of many natural products of clinical interest involves large, multi-domain enzymes called nonribosomal peptide synthetases (NRPSs). In bacteria, many of the gene clusters coding for NRPSs also code for a member of the MbtH-like protein superfamily, which are small proteins of unknown function. Using MbtH-like proteins from three separate NRPS systems, we show that these proteins co-purify together with the NRPSs and influence amino acid activation. As a consequence, MbtH-like proteins are integral components of NRPSs.Nonribosomal peptide synthetases (NRPSs) are involved in the assembly of natural products of clinical interest such as the antibacterial drugs vancomycin, daptomycin, and capreomycin. A basic understanding how NRPSs catalyze the assembly of such molecules from simple precursors has been established (1). During assembly, each precursor is activated, covalently tethered to the NRPS, and then directionally condensed into the growing molecule by a set of catalytic domains grouped together as modules. Each module is typically composed of an adenylation (A) domain that recognizes and activates each precursor and tethers them to a peptidyl carrier protein (PCP) domain as a thioester. Condensation (C) domains subsequently catalyze directional bond formation between two PCP-linked precursors. Additional domains can add functionality to the precursors or govern its release from the NRPS. The repeating domain/modular structure of NRPSs provides an assembly line-like logic to the biosynthesis of the associated natural products.In bacteria, many gene clusters coding for the NRPS involved in the production of natural products also code for a small (∼70 amino acid) protein containing three conserved tryptophan residues. These proteins have been named the MbtH-like protein superfamily based on their similarity to MbtH from the mycobactin biosynthesis gene cluster (2). The production of some NRPS-dependent natural products requires an MbtH-like protein (3,4), but how these proteins influence production is unknown. Co-production of an MbtH-like protein with an NRPS component enhances protein production levels (5). A direct role in catalysis has been questioned by a report that the enterobactin (ENT) NRPS is functional in vitro in the absence of the associated MbtH-like protein (6). Structural work on the MbtHlike protein from the pyroverdine system (3) and MbtH itself (7) did not reveal any motifs suggestive of a catalytic site, instead, a role in protein-protein interactions.We are investigating the biosynthesis of the antituberculosis drugs capreomycin (CMN) and viomycin (VIO) to better understand NRPS enzymology and develop new derivatives of these drugs using combinatorial biosynthesis. These structurally related non-ribosomal * To whom correspondence should be addressed. Phone: (608) Figure S1, Supporting Information) (8, 9). In addition to the NRPS components, the associated gene clusters code for MbtH-like proteins. This provided us with two related NRPS systems to address questions co...

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The gut microbiome has been known to contribute up to ~30% of the energy absorption of the host. Although various beneficial mechanisms of probiotics have been suggested for non-alcoholic fatty liver disease (NAFLD), whether and which probiotics impact the host’s intestinal energy absorption have not yet been quantitatively studied. Here, we suggest a novel mechanism of probiotics against NAFLD, in which Lactobacillus rhamnosus GG, the most common probiotic, shares intestinal fatty acids and prevents the development of diet-induced hepatic steatosis. By using quantitative methods (radioactive tracers and LC–MS) under both in vitro and in vivo conditions, we found that bacteria and hosts competed for fatty acid absorption in the intestine, resulting in decreased weight gain, body fat mass, and hepatic lipid accumulation without differences in calorie intake and excretion in mice fed the probiotic bacteria.

In the past decade, the incidence of type 2 diabetes (T2D) has rapidly increased, along with the associated cardiovascular complications. Therefore, understanding the pathophysiology underlying T2D, the associated complications and the impact of therapeutics on the T2D development has critical importance for current and future therapeutics. The prevailing feature of T2D is hyperglycemia due to excessive hepatic glucose production, insulin resistance, and insufficient secretion of insulin by the pancreas. These contribute to increased fatty acid influx into the liver and muscle causing accumulation of lipid metabolites. These lipid metabolites cause dyslipidemia and non-alcoholic fatty liver disease, which ultimately contributes to the increased cardiovascular risk in T2D. Therefore, understanding the mechanisms of hepatic insulin resistance and the specific role of liver lipids is critical in selecting and designing the most effective therapeutics for T2D and the associated co-morbidities, including dyslipidemia and cardiovascular disease. Herein, we review the effects and molecular mechanisms of conventional anti-hyperglycemic and lipid-lowering drugs on glucose and lipid metabolism. [BMB Reports 2016; 49(3): 139-148]