Re: O/T:Scientists Discover Natural Antibiotic in Human Gut

[Guest guest]

Interesting find , here is what it says on PubMed:

Nat Immunol 2003 Jan 27; [epub ahead of print]

Angiogenins: a new class of microbicidal proteins involved in innate immunity.

Hooper LV, Stappenbeck TS, Hong CV, Gordon JI.

Department of Molecular Biology and Pharmacology, Washington University School

of Medicine, St. Louis, MO 63110, USA.

Although angiogenins have been implicated in tumor-associated angiogenesis,

their normal physiologic function remains unclear. We show that a previously

uncharacterized angiogenin, Ang4, is produced by mouse Paneth cells, is secreted

into the gut lumen and has bactericidal activity against intestinal microbes.

Ang4 expression is induced by Bacteroides thetaiotaomicron, a predominant member

of the gut microflora, revealing a mechanism whereby intestinal commensal

bacteria influence gut microbial ecology and shape innate immunity. Furthermore,

mouse Ang1 and human angiogenin, circulating proteins induced during

inflammation, exhibit microbicidal activity against systemic bacterial and

fungal pathogens, suggesting that they contribute to systemic responses to

infection. These results establish angiogenins as a family of endogenous

antimicrobial proteins.

PMID: 12548285 [PubMed - as supplied by publisher]

O/T:Scientists Discover Natural Antibiotic in Human Gut

More from Wash U --- researchers discover a naturally-occuring anti-

biotic that may well pave the way for newer and better antiobitics:

Scientists Discover Natural Antibiotic in Human Gut

Mon Jan 27

By Carroll

NEW YORK (Reuters Health) - Researchers have found a potent

antibacterial protein that is made naturally by the human body.

The protein, dubbed Ang4, is created by cells in the intestines,

according to a study published in the advance online version of the

journal Nature Immunology.

//truncated for space allocation//

____________

Source: Nature Immunology online edition 2003;10.1038/ni888.

Responsibility for the content of this message lies strictly with

the original author, and is not necessarily endorsed by or the

opinion of the Research Institute.

[Guest guest]

Hi Jon,

I found a few interesting things when I was looking on Pubmed. It discusses

other members of the family. Some with the bacterial effects and also

against retroviruses. The entries link to RNASE L, (part of the anti-viral

pathway) some of the research has found an unusual form elevated in CFS.

I'm not sure if it's connected to this, although there is alot of research

connecting retrovirus antibodies to disorders like MS, CFS, Lupus,

arthritis, Schizophrenia, etc. Some of the research mentions endogenous

viruses protecting against exogenous ones.

Well I'll stop rambling.... I've included some of the things I was looking

at in case you're interested.

Cheryl

--------------------------------------------------------------------

RNase k6

Gene map locus Chr.14

TEXT

Rosenberg and Dyer (1996) identified ribonuclease 6, which they referred to

as RNase k6, as an unexpected result of their efforts to trace the

evolutionary history of the ribonuclease gene family. RNASE6 encodes a

150-amino acid polypeptide most closely related to ribonuclease 2 (RNASE2;

131410); these 2 genes share 47% amino acid sequence identity. Other human

ribonuclease family members include pancreatic ribonuclease (RNASE1;

180440), ribonuclease 3 (RNASE3; 131398), angiogenin (ANG; 105850), and

ribonuclease L (RNASE4; 601030). RNASE6 mRNA was detected in all human

tissues tested, with lung representing the most abundant source. The authors

used a PCR-based technique to map RNASE6 to chromosome 14.

RNS2

EOSINOPHIL-DERIVED NEUROTOXIN; EDN

Gene map locus 14q24-q31

TEXT

CLONING

Eosinophil-derived neurotoxin is a distinct cationic protein of the

eosinophil's large specific granule known primarily for its ability to

induce ataxia, paralysis, and central nervous system cellular degeneration

in experimental animals (Gordon phenomenon). Rosenberg et al. (1989)

isolated a 725-bp cDNA clone for EDN. The open reading frame encodes a

134-amino acid polypeptide with a molecular mass of 15.5 kD and a 27-residue

N-terminal hydrophobic leader sequence. The sequence of the mature

polypeptide was identical to that reported for human urinary ribonuclease

and to the N-terminal sequence of human liver ribonuclease. Similarities to

the ribonucleases of pancreas (180440) and angiogenin (105850) indicate that

EDN belongs to the ribonuclease multigene family. This gene is also

symbolized RNS2 for ribonuclease 2. Hamann et al. (1990) demonstrated the

close similarities between the genes encoding eosinophil-derived neurotoxin

and another eosinophil granule protein, eosinophil cationic protein (RNS3;

131398).

EVOLUTION

Zhang and Rosenberg (2002) investigated the evolution of the 2 genes RNASE2

and RNASE3 that evolved through a duplication event about 31 million years

ago in the evolutionary lineage of hominoids and Old World monkeys. Only 1

copy of the EDN/ECP (RNS3) gene exists in the genomes of New World monkeys

and prosimians.

In a commentary on the work of Zhang and Rosenberg (2002), Benner (2002)

noted that the pair of proteins are relatives of digestive ribonuclease in

artiodactyls, the mammalian order containing ox, giraffe, deer, and

antelope. This digestive ribonuclease was evidently created approximately 40

million years ago, when ruminant digestion first emerged, to degrade the RNA

from bacteria growing in the rumen. ECP kills bacteria in vitro; EDN

inactivates retroviruses in vitro.

GENETIC VARIABILITY

Zhang and Rosenberg (2002) showed that the mother gene of the duplicated

genes had already possessed a weak antiviral activity before duplication.

After duplication, substitutions at 2 interacting sites (arg64 to ser and

thr132 to arg) resulted in a 13-fold enhancement of the ribonucleolytic

activity of eosinophil-derived neurotoxin.

These substitutions are also necessary for the potent antiviral activity,

with contributions from additional amino acid changes at interacting sites.

Zhang and Rosenberg (2002) found that change in EDN function occurred only

when both interacting sites were altered, indicating the importance of

complementary substitutions in protein evolution. Thus, neutral

substitutions are not simply 'noises' in protein evolution.

They may play constructive roles by setting the intramolecular

microenvironment for further complementary advantageous substitutions.

Although individually the 2 replacements at sites 64 and 132 have little

impact on behavior, each provided the context for the other to have a

consequence. Thus, an inconsequential replacement may set the stage for a

second adaptive replacement. Benner (2002) commented on the usefulness of

correlating events in molecular history with events in the geologic and

paleontologic records.

Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 8, 5486-5491, April 16, 2002

From the Cover

Evolution

Complementary advantageous substitutions in the evolution of an antiviral

RNase of higher primates

Jianzhi Zhang*,, and Helene F. Rosenberg*

* Laboratory of Host Defenses, National Institute of Allergy and Infectious

Diseases, National Institutes of Health, Bethesda, MD 20892; and

Departments of Ecology and Evolutionary Biology and Molecular, Cellular, and

Developmental Biology, University of Michigan, Ann Arbor, MI 48109

http://www.pnas.org/cgi/content/full/99/8/5486

------------------------------------------------------------------------

Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 8, 4760-4761, April 16, 2002

Commentary

The past as the key to the present: Resurrection of ancient proteins from

eosinophils

A. Benner*

Department of Chemistry, University of Florida, Gainesville, FL 32611-7200

SNIP...

Indeed, the function of eosinophils as cells remains enigmatic (6). We know

much about their activities in allergic disease. Eosinophils are associated

with asthma, infective wheezing, and eczema, for example (7), but cells do

not exist to create diseases. When they function correctly, our own cells

must contribute to our evolutionary fitness; helping us survive, select a

mate, and reproduce. A current hypothesis suggests that eosinophils do this

by defending us from outside agents, with allergic diseases arising as an

undesired side effect. Beyond this, we can say very little.

Earlier work by Zhang, Rosenberg, and their associates (6, 8) had already

suggested that ECP and EDN might contribute to fitness in new and

differentiated ways, some possibly associated with defense.

ECP kills bacteria in vitro;

EDN inactivates retroviruses in vitro (6).

In silico analysis of reconstructed ancestral sequences in primates

suggested that the proteins had suffered rapid sequence change near the time

of the duplication that generated these two proteins, a change that might

account for their differing behaviors in vitro (8). Ignoring, for the sake

of discussion, some technical issues, this observation suggests that in

primate evolution, mutant forms of EDN and ECP conferred more fitness than

unmutated forms. This finding indicates that these proteins have roles, and

that their roles were changing, adapting, and specializing during the

episodes of rapid sequence evolution.

SNIP>>

This change may have favored ruminant digestion, which provides another

example of recruitment in the ECP/EDN superfamily. If EDN, ECP, and

eosinophils are part of a defensive system, it is appropriate to ask what

happened during the Oligocene that might have encouraged this type of system

to be selected?

Why might new defenses against retroviruses be needed at this time? Defenses

against bacteria?

http://www.pnas.org/cgi/content/full/99/8/4760

----Original Message Follows----

From: " Jon " <jerseybean@...>

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Subject: Re: O/T:Scientists Discover Natural Antibiotic in Human Gut

Date: Tue, 28 Jan 2003 19:30:44 -0000

Interesting find , here is what it says on PubMed:

Nat Immunol 2003 Jan 27; [epub ahead of print]

Angiogenins: a new class of microbicidal proteins involved in innate

immunity.

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